Prostenoic acids and esters

ABSTRACT

This disclosure describes derivatives, analogs, and congeners of prostanoic acid having a terminal cyclic moiety in the β-chain which possess the pharmacological activities associated with the prostaglandins.

BACKGROUND OF THE INVENTION

Applicants are not aware of any prior art reference which, in theirrespective judgments as one skilled in the prostaglandin art, wouldanticipate or render obvious the novel compounds of the instantinvention; however, for the purpose of fully developing the backgroundof the invention and establishing the state of the requisite art, thefollowing references are set forth: U.S. Pat. No. 3,884,969; JapanesePat. No. 3,884,969; German Offen. No. 2,515,770; German Offen. No.2,510,818; and Netherlands published Patent Application No. 7,410-185.

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel prostenoic acids and esters of theformula: ##STR1## wherein V is selected from the group consisting of##STR2## R₁ is selected from the group consisting of hydroxy,triloweralkylsilyloxy (C₁ to C₄) and straight or branched chain alkoxy(C₁ to C₆); Y is a trivalent radical selected from the group consistingof ##STR3## wherein R₃ is selected from the group comprising hydrogen,triloweralkylsilyl and alkanoyl (C₂ to C₅); X is a divalent radicalselected from the group comprising ##STR4## wherein R₄ is selected fromthe group consisting of a branched or straight chain alkyl group (C₁ toC₇), hydrogen, phenoxy and phenoxy substituted with a compound selectedfrom the group consisting of halogen, trifluoromethyl, and methoxy; n iszero or an integer from 1 to 4; m is zero or an integer from 1 to 4; thesum of n and m has the value of 2 to 4; the moiety C₁₃ -C₁₄ is ethyleneor trans vinylene; w is 1 or zero, Z is a divalent radical selected fromthe group consisting of -- (CH₂)_(p) --, ##STR5## --(CH₂)_(t) --O--CH₂-- and --(CH₂)_(t) --S--CH₂ --wherein p is an integer from 5 to 7, q isan integer from 1 to 3, t is an integer from 3 to 5.

DETAILED DESCRIPTION OF THE INVENTION

Useful pharmacologically acceptable salts of the above formula whereinR₁ is hydroxy are those with pharmacologically acceptable metal cations,ammonium, amine cations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium and potassium, and from the alkaline earthmetals, e.g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum zinc, and iron, are within the scope of thisinvention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, and the aliphatic, cycloliphatic,and araliphatic amines containing up to an including about 18 carbonatoms, as well as heterocyclic amines, e.g., piperidine, morpholine,pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g.,1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine,2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and thelike, as well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di, and triethanolamine, ethyldiethanolamine,N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine,N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

The compounds of this invention are administered in various ways forvarious purposes, e.g., intravenously, intramuscularly, subcutaneously,orally, intravaginally, rectally, bucally, sublingually, topically andin the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonicsolutions are preferred. For that purpose, it is preferred because ofincreased water solubility that R₁ be hydrogen or a pharmacologicallyacceptable cation. For subcutaneous or intramuscular injection, sterilesolutions or suspensions of the acid, salt, or ester formed in aqueousor non-aqueous media are used. Tablets, capsules, and liquidpreparations such as syrups, elixirs, and simple solutions, with theusual pharmaceutical carriers are used for oral or sublingualadministration. For rectal or vaginal administration, suppositoriesprepared as known in the art are used. For tissue implants, a steriletablet or silicone rubber capsule or other object containing orimpregnated with the substance is used. On certain occasions it may beadvantageous to administer the compounds of this invention as clathratecompounds with substances such as α-cyclodextrin.

The prostaglandins are a family of closely related compounds which havebeen obtained from various animal tissues and which stimulate smoothmuscle, lower arterial blood pressure, antagonize epinephrine-inducedmobilization of free fatty acids, and have other pharmacological andautopharmacological effects in mammals. See Bergstrom, et al., J. Biol.Chem., 238, 3555 (1963) and Horton, Experientia, 21, 113 (1965) andreferences cited therein. All of the so-called natural prostaglandinsare derivatives of prostanoic acid: ##STR6## The hydrogen atoms attachedto C-8 and C-12 are in trans-configuration. The natural prostaglandinsrepresent only one of the possible optical isomers. The compounds ofthis invention include all possible optical isomers.

The compounds of this invention which have the structure as shown informula (A) wherein R, Z, R₂, R, m, n, w and x are as herein abovedefined are said to be in the same configuration as the naturalprostaglandins with respect to the configurations at C₈ and C₁₂ and aredesignated by the prefix nat. The enantiomer, represented by formula (B)is said to be in the mirror image or ent configuration. A cyano group atC₁₁ drawn with a dotted line (C₁₁ ---C_(N)) is said to have an αconfiguration; a solid line (C₁₁ --CN) indicated a β configuration. Theconfiguration at Y and X will be expressed in terms of R and S as isunderstood in the art. For example, the compound represented by formula(C) is named:nat-15S,16S-15-dihydroxy-9-oxo-15,16-trimethylene-13-trans-10-prostadienoicacid; its enantiomer (formula D) is namedent-15R,16R-15-dihydroxy-9-oxo-15,16-trimethylene-13-trans-10-prostadienoicacid. The racemate [1:1 mixture of (C) and (D)] is namednat-15S,16S-(andent-15R,16R)15-dihydroxy-9-oxo-15,16-trimethylene-13-trans-10-prostadienoicacid. In a similar manner, the compounds represented by formulae (E) to(J) have the configurations shown below. ##STR7##

The novel compounds of this invention can be prepared by the reactionsequences illustrated in Flowsheet A below, wherein n, m, X, w and Z areas hereinabove defined; R₁ ' is straight or branched-chain alkoxy (C₁ toC₁₂) or triloweralkylsilyloxy (C₁ to C₄); R₂ ' is triloweralkylsilyloxy(C₁ to C₄) or alkanoyloxy (C₂ to C₅); R₁ " and R₂ " are hydroxy.##STR8##

In accordance with the scheme as outlined hereinabove in Flowsheet A aketone (I) is reacted with a Grignard reagent (II) such as acetylenemagnesium chloride (II, w=0) or propargyl magnesium bromide (II, w=1) togive the acetylenic alcohols (III). In those cases where X is not --CH₂-- two isomeric acetylenic alcohols are formed. These isomers can beseparated by procedures well known to the art including fractionalcrystallization, fractional distillation and various chromatographicprocedures. The individual isomers can then be carried through theremaining reactions outlined in Flowsheet A.

The acetylenic alcohol (III) is converted to its trimethylsilyl ether inthe usual manner. The silylated derivative (IV) is then treated withdiisoamylborane (prepared in situ in tetrahydrofuran solution at icebath temperatures from 2-methyl-2-butene, sodium borohydride and borontrifluoride ethereate) and then anhydrous trimethylamine oxide. Theresulting solution and an iodine solution in tetrahydrofuran are thenadded simultaneously to an aqueous solution of sodium hydroxide to givethe 1-iodo-3-trimethylsilyloxy-trans-1-alkene (V).

The vinyl iodide (V) is converted to the trans-vinyl lithium derivative(VII) with clean retention of configuration by treatment at about -78°C. in hexane or toluene solution with either one equivalent of n-butyllithium or two equivalents of t-butyl lithium. It is preferable for thistreatment to proceed for about one hour at -78° C., then for about onehour at -40° C. and finally for about one hour at about 0° C. For thesubsequent preparation of lithio alanate reagents (VIII) it ispreferable to use n-butyl lithium, and for the lithio cuprate reagents(IX) or (X) t-butyl lithium is the agent of choice. The same vinyllithium derivative (VII) can be prepared from the 1-tri-n-butylstannyl3- trimethylsilyloxy-trans-1-alkene (VI) by treatment of (VI) withn-butyl lithium in hexane solution at -40° to 0° C. (VI) in turn isreadily prepared by the addition of tri-n-butyl tin hydride to theacetylene (IV) in the presence of bisazoisobutyronitrile followed byvacuum distillation at a high enough temperature (about 170° C.) toisomerize any of the cis-vinyl tin compound to the trans-vinyl tincompound.

For the preparation of the alanate reagent (VIII) or the like, a molarequivalent of a tri-lower alkyl (1-5 carbon atoms) aluminum (e.g.,trimethyl aluminum), dissolved in a solvent such as hexane, is added tothe vinyl lithium derivative (VII) at about 0° C. After about 15-45minutes at this temperature the requisite blocked cyclopentenone (XI) isadded and the reaction mixture is stirred for about 18 hours at ambienttemperatures. The mixture is quenched with aqueous hydrochloric acid inthe cold and the product is obtained by extraction. In the 11-deoxyseries the blocking trialkylsilyl group is removed on treatment withacetic acid: tetrahydrofuran:water (4:2:1) at room temperatures forabout twenty minutes. The ester group can then be saponified in theusual manner. In the 11-oxy series, the silyl groups are removed bytreatment with acetic acid:water:tetrahydrofuran (20:10:3) at about 40°C. for about 4 hours. Alkyl esters of the 11-oxy series are notdisturbed by this treatment and cannot be saponified by chemical meansin view of the instability of the 11-hydroxy-9-ketone to base treatment.However, the ester can be cleaved by treatment with Baker's Yeast, aprocedure well-known in the art.

For the preparation of the asymmetrical lithio cuprate (IX) or the like,a solution of one molar equivalent of copper (I)-1-alkyne, preferablycopper (I)-1-pentyne, in anhydrous hexamethylphosphorous triamide,preferably three to five molar equivalents, and anhydrous ether is addedto one molar equivalent of the aforementioned vinyl lithium (VII)solution cooled to about -78° C. The solution is then stirred for aboutone hour at -78° C. A cuprate reagent containing a p-thiophenoxideligand ##STR9## can also be used; it is prepared by first forminglithium thiophenoxide by adding an equivalent of n-butyl lithium inhexane to an etheral solution of thiophenol. To this is then added asolution of one equivalent of tri-n-butyl phosphine copper iodidecomplex in ether. The resulting solution of phenylthio copper is addedat -78° C. under inert gas to the solution of the vinyl lithium compound(VII). The mixture is then maintained at -78° C. for one hour. To eitherof these cuprate solutions at -78° C. a molar equivalent of therequisite cyclopentenone (XI) is added. After several hours at -20° C.the reaction mixture is quenched with aqueous ammonium chloride solutionand the blocked product (XII) is isolated in the usual manner. Thedeblocking of this product is then carried out in the manner asdescribed hereinabove.

The products are finally purified by chromatographic procedures in theusual manner.

In those cases where X is not CH₂ and m≠n-1, two isomers are formedwhich differ in the configuration at C₁₅ or C₁₆ ; both isomers areracemates and they can be separated from each other by chromatographicprocedures well known in the art.

For the preparation of the symmetrical lithion cuprate (X) one molarequivalent of copper (I) iodide tributylphosphine complex, dissolved inanhydrous ether, is added at about -78° C. to two molar equivalents ofthe aforementioned vinyl lithium (VII) solution in hexanes, cooled to-78° C. After about one hour at this temperature, the lithio cuprate (X)is treated with the requisite cyclopentenone (XI) as des cribedhereinabove for the conjugate addition with the 1-alkynyl lithio cuprate(IX).

In order to ensure a trans-relationship in (XII), (XIV) or (XIII), theseproducts can be submitted to conditions known in the literature toequilibrate cis 8-iso-PGE₁ to a mixture contaning about 90% of thetrans-product [see E. G. Daniels, et al., J. A. C. S., 90, 5894 (1968)].These conditions involve treatment with potassium acetate in aqueousmethanol for about 96 hours at room temperature. The cis and transproducts are separable by chromatographic procedures.

Most of the cyclopentenones required for the purposes of this inventionhave been described in the literature or can be prepared by proceduresquite analogous to those already described. Appropriate references areprovided in the examples which follow. The synthesis of certainnonreference requisite cyclopentenones is also described therein.

Treatment of the 11-hydroxy derivatives represented by formulae (XIV) or(XIII) in which R₂ " is hydroxy with dilute acid results in dehydrationof the β-ketol system and the formation of the corresponding Δ¹⁰derivatives (XVI) or (XV) (prostaglandins of the A type). A preferredprocedure involves treatment in tetrahydrofuran:water (2:1) solvent 0.5Nin hydrochloric acid for about twenty hours at ambient temperatures.Under these conditions tetrahydropyranyl or trialkylsilyl esters undergohydrolysis if this procedure is applied to the initial conjugateaddition product (XII). More prolonged treatment with acid or preferablytreatment with dilute base, e.g., sodium carbonate in aqueous methanolor an amine such as piperidine, effects the conversion of (XIV) or(XIII) to the Δ⁸(12) derivatives (XVIII) or (XVII) (prostaglandins ofthe B type). The Δ¹⁰ derivatives (XVI) and (XV) can also be prepared bypreforming a conjugated addition of cuprate (IX) (L=--C.tbd.CC₃ H₇ ) tothe cyclopentenone (XI) (R₂ 40 is trimethylsilyloxy) as described hereinabove and allowing the resulting solution to reach a temperature of 0°C. for 1-2 hours. Under these conditions, both conjugate addition andelimination of the C₁₁ trimethylsilyloxy group occurs; after deblockingas described hereinabove, the Δ¹⁰ derivatives (XVI) and (XV) areisolated and separated by chromatographic procedures.

The 13-dihydro derivatives (C₁₃ -C₁₄ is ethylene) of this invention canbe prepared by reduction of the Δ¹³ function in the corresponding13-prostenoic acids or esters.

Compounds of this invention which contain a cyano group at C₁₁ areprepared by reacting the corresponding Δ¹⁰ derivative with acetonecyanohydrin and a base catalyst such as sodium carbonate.

The prostanoic and prostenoic carboxylic acids of this invention areconvertible to the corresponding alkyl esters by treatment with theappropriate diazoalkane in the usual manner. The preparation ofdiazoalkanes by various procedures are well-described in the art, seefor example C. D. Gutsche, Organic Reactions, VIII, 389 (1954). Certainof the esters of this invention can also be obtained directly by use ofthe appropriate cyclopentenone ester (see XI). The various esters canalso be prepared by any of several procedures well-known in the art viaan acid chloride (prior blocking of free alcohol groups with appropriateblocking groups such as trialkylsilyl, tetrahydropyranyl and the like)or mixed anhydrides and treatment of these intermediates with theappropriate alcohol. Mixed anhydrides can be obtained by treatment ofthe prostaglandin acid in a solvent such as dioxane at a temperature inthe range of 0° C. to 15° C. with a molar equivalent of atri-alkylamine, preferably triethylamine, tributylamine and the like,and then a molar equivalent of isobutyl chlorocarbonate or the like. Theresulting mixed anhydride is then treated with the appropriate alcoholto give the derivatized product. [For a pertinent literature analogy seeProstaglandins, 4, 738 (1973).]

An alternative procedure involves treatment of the prostaglandin acidwith a molar equivalent of the trialkyl amine in an excess of theappropriate alcohol in an anhydrous solvent such as methylene chloride,a molar equivalent of p-toluenesulfonyl chloride is then added (ifnecessary, a second molar equivalent can be added) and after stirring atambient temperatures for about 15 minutes to one hour the product isworked-up in the usual manner. (For a pertinent literature analogy seeU. S. Patent 3,821,279, June 28, 1974). A third procedure involves useof dicyclohexylcarbodiimide in the usual manner; for a pertinentliterature analogy see German Offen. 2,365,205 (July 11, 1974); Chem.Abst., 81, 120098 g. (1974).

Certain of the ketones (I) of this invention are prepared as indicatedin Flowsheet B below: ##STR10## wherein n and m are as hereinabovedefined and the moiety ##STR11## represents a phenoxy group which isoptionally substituted with one or more halogen, trifluoromethyl, andlower alkyloxy (C₁ to C₄) groups.

As indicated in Flowsheet B the reaction of an epoxide (XXV) with asubstituted or unsubstituted phenol (XXVI) in the presence of acatalytic amount of aqueous sodium hydroxide and a phase transfercatalyst such as methyl tricapryly ammonium chloride and the like at 70°-80° C. gives the phenoxy substituted alcohol (XXVII) which in turn isoxidized with an oxidizing reagent such as pyridinium chlorochromate inmethylene chloride to give the phenoxy substituted ketone (XXVIII).

The other ketones (I) used in this invention are known in the literatureor can be made by procedures well known to the art [G. Lardeli, U.Lamberti, W. T. Walles and A. P. de Jonge, Rec. Trav. Chem. Pays-Bas, 86481 (1976); Ng. Ph. Buu-Hoi, T. B. Loc and Ng. Dat Xuong., Bull. Soc.Chem. France, 174 (1958); and G. H. Posner, Organic Reactions, 19, 1(1972)].

Also embraced within the scope of this invention are the variousintermediates, the use of which is described herein. These arerepresented by the following generic formulae (K) and (L). ##STR12##Wherein w, n, m and X are as hereinabove defined; R₆ is lower alkyl (C₁to -C₆); Q is iodine, triloweralkyl (C₁ -C₆) tin, lithium, ##STR13## R₇is lower alkyl (C₁ -C₇).

When the compounds of this invention are prepared from racemic startingcompounds two racemates are obtained. In appropriate instances theseracemates can be separated from each other by careful application of theusual chromatographic procedures. In the more difficult instances it maybe necessary to apply high pressure liquid chromatography includingrecycling techniques. [See G. Fallick, American Laboratory, 19-27(August, 1973) as well as references cited therein. Additionalinformation concerning high speed liquid chromatography and theinstruments necessary for its application is available from WatersAssociate, Inc., Maple Street, Milford, Mass.]

It is also possible to prepare the individual enantiomers in the 11-oxyseries via the conjugate addition procedure discussed above by startingwith a resolved 4-oxycyclopentenone [see (XI), R₂ ' istri-loweralkylsilyloxy]. The resulting products (XIV) and (XIII) afterdeblocking as described hereinabove are obtained in their opticallyactive forms.

The 4-hydroxycyclopentenone racemates may be resolved into theircomponent enantiomers (XXXI) and (XXXII) by derivatizing the ketonefunction with a reagent having an optically active center. The resultingdiastereomeric mixture can then be separated by fractionalcrystallization, or by chromatography, or by high speed liquidchromatography involving, if necessary, recycling techniques. Among theuseful optically active ketone derivatizing reagents are1-α-aminoxy-ν-methylpentanoic acid hydrochloride [to give (XXXIII)],(R)-2-aminoxy-3,3-dimethylbutyric acid hydrochloride, and4-α-methylbenzyl semicarbazide. After separation of the diastereomericderivatives, reconstitution of the keto function provides the individual4-hydroxycyclopentenone enantiomers (XXXI) and (XXXII). A usefulprocedure for the resolution of a 4-hydroxycyclopentenone racemate viaan oxime such as (XXXIII) is described in the art [R. Pappo, P. Collinsand C. Jung, Tetrahedron Letters, 943 (1973)]. ##STR14##

An alternative procedure for the preparation of the4(R)-hydroxycyclopentenone enantiomers such as (XXXI) involves as a keystep the selective microbiological or chemical reduction of trione(XXXIV) to the 4(R)-hydroxycyclopentanedione (XXXV). A wide variety ofmicroorganisms are capable of accomplishing this asymmetric reduction,one of the most useful being Dipodascus unincleatus. This step also canbe achieved chemically by catalytic hydrogenation in the usual manner(for example, under about one atmosphere of hydrogen in methanol) usinga soluble rhodium catalyst with chiral phosphine ligands, such as(1,5-cyclooctadiene)-bis-(o-anisylcyclohexylmethylphosphine)rhodium (I)tetrafluoroborate in the presence of one equivalent of organic base,such as triethylamine.

Conversion of hydroxycyclopentanedione (XXXV) to an enol ether or enolester, (XXXVI, E=alkyl, preferably iso-propyl; aroyl such as benzoyl; orarylsulfonyl such as 2-mesitylenesulfonyl), is accomplished bytreatment, for example, with isopropyl iodide and a base such aspotassium carbonate in refluxing acetone for from 15 to 20 hours, orwith a base such as triethylamine and 0.95 equivalents of benzoylchloride or a slight excess of 2-mesitylenesulfonyl chloride in anon-prototropic solvent at a temperature of about -10° to -15° C.Reduction of (XXXVI) with excess sodium bis(2-methoxyethoxy)aluminumhydride in a solvent such as tetrahydrofuran or toluene at lowtemperatures, such as -60° to -78° C., followed by mild acid hydrolysis(representative conditions: aqueous dilute hydrochloric acid, pH 2.5; oroxalic acid, sodium oxalate in chloroform) at ambient temperatures from1 to 3 hours provides the 4(R)-hydroxycyclopentenone ester (XXXVII). Theester (XXXVII), after blocking the hydroxy function as describedhereinabove, can be subjected to conjugate addition reactions also asdescribed hereinabove. The conjugate addition product, after deblockingthe 11- and 15-hydroxy groups, will then be a methyl ester which can behydrolyzed to the corresponding carboxylic acid by enzymatic ormicrobiological procedures, for example with baker's yeast or byexposure to Rhizopus oryzae.

For a description of these procedures in the art see: C. J. Sih, et al,J. A. C. S., 95, 1676 (1973); J. B. Heather, et al., TetrahedronLetters, 2213 (1973); R. Pappo and P. W. Collins, Tetrahedron Letters,2627 (1972); and R. Papo, P. Collins, and C. Jung, Ann. N. Y. Acad.Sci., 180, 64 (1974). For a description of the baker's yeast proceduresee C. J. Sih, et al. J. A. C. S., 94, 3643 (1972). ##STR15##

Procedures for the preparation of the requisite cyclopentanetriones(XXXIV) are well-established in the art and generally involve thetreatment of an -1 oxo long chain ester (XXXVIII) with methyl or ethyloxalate and a base such as sodium methoxide in methanol, followed bytreatment with dilute hydrochloric acid in aqueous methanol to effectthe dealkoxalylation of the intermediate (XXXIX). See J. Kutsube and M.Matsui, Agr. Biol. Chem., 33 1078 (1969); P. Collins, C. J. Jung and R.Pappo, Israel Journal of Chemistry, 6, 839 (1968); R. Pappo, P. Collinsand C. Jung, Ann. N. Y. Acad. Sci., 180, 64 (1971); C. J. Sih, et al.,J. A. C. S., 95, 1676 (1973) (see reference 7); and J. B. Heather, etal., Tetrahedron Letters, 2313 (1973) for pertinent backgroundliterature. ##STR16##

The intermediate keto esters (XXXVIII) may be prepared by a variety ofmethods known to the art. One useful procedure is outlined below andinvolves alkylation of ethyl acetoacetate sodium salt (XL) in the usualmanner with the appropriate side-chain precursor (XLI, X═C1, Br, I,preferably Br or I) followed by decarbethoxylation and reesterification,all in the usual manner. ##STR17##

The side-chain precursors (XLI) are commercially available where Z is--(CH₂)_(p) --, and can be prepared as described in Belgian Pat. No.786,215 (granted and opened to inspection Jan. 15, 1973).

Those precursors wherein Z is --(CH₂)_(t) --O--CH₂ -- can be prepared bythe transformation shown directly below starting with themono-tetrahydropyranyl derivative (XLIV). Thus, (XLIV) is converted tothe lithium alcoholate by treatment with butyl lithium, the alcoholateis then O-alkylated with ethyl bromoacetate to provide (XLV), which onde-O-tetrahydropyranylation, mesylation and reaction with lithiumbromide gives the required (XLVI). (These and all the above-describedtransformations can be effected in the usual manner, well-established inthe art; pertinent examples for most of the reactions can be found inthe above-cited Belgian Pat. No. 786,215.) ##STR18##

It is also possible to resolve the 4-hydroxycyclopentenone racemate(XLIX) by microbiological means. Thus, treatment of the 4O-alkanoyl oraroyl derivatives (L, R₁₈ =aryl or alkyl) of racemate (XLIX) (preferablythe 4O-acetyl and 4-O-propionyl derivatives) with an appropriatemicroorganism, preferably a Saccharomyces species e.g., 1375-143,affords preferential de-O-acylation of the 4(R)-enantiomer to give (LI),which is then separated from the unreacted 4(S)-O-acyl enantiomer (LII)by chromatographic procedures. After separation, mild hydrolysis of the4(S) derivative (LII) provides the 4(S)-hydroxycyclopentenone (LIII).[See N. J. Marsheck and M. Miyano, Biochima et Biophysica Acta, 316, 363(1973) for related examples.] ##STR19##

It is also possible to prepare the individual 4-hydroxycyclopentenones(LI) and (LIII) directly by selective microbial hydroxylations of thecorresponding 4-unsubstituted cyclopentenone (LIV). For example, withAspergillus niger ATCC 9142; a selective 4(R)-hydroxylation of [LIV,Z=(CH₂)₆ ] has been reported; see S. Kurozumi, T. Tora and S. Ishimoto,Tetrahedron Letters, 4959 (1973). Other microorganisms can alsoaccomplish this hydroxylation. ##STR20##

An alternative resolution procedure involves derivatization of thealcohol function of the racemic hydroxycyclopentenone to give ester-acidderivatives such as (LV) wherein R₁ " is hydrogen or an alkoxy group, n'is zero or two and z is as hereinabove defined. ##STR21##

Such derivatives may be obtained from the corresponding freehydroxycyclopentenone by treatment in the usual manner with oxalylchloride, succinyl chloride, succinic anhydride and the like. Treatmentof the resulting acid or diacid (R₁ "=hydrogen) with optically activeamines e.g., 1-(-)-α-methylbenzylamine, d-(+)-α-methylbenzylamine,brucine, dehydroabietylamine, strychnine, quinine, cinchonine, quinidineephedrine, (+)-α-amino-1-butanol and the like, and fractionalrecrystallization of the resulting diastereomeric mixtures followed bycleavage of the 4-oxy ester function in each of the individuallyisolated diastereomers provides the individual 4(R)- and4(S)-hydroxycyclopentenone enantiomers (LVI) and (LVII) or theirrespective esters. Cleavage of the oxalate acid ester (LV, n=O) can beaccomplished by treatment with lead tetraacetate in pyridine solution.For an example of a similar use of oxalate acid-esters see J. G.Molotkovsky and L. D. Bergelson, Tetrahedron Letters, 4791 (No. 50,1971); For an example of the use of a succinate acid-ester see B.Goffinet, Ger. Offen. No. 2,263,880; Chem. Abstracts, 79, 7815_(z)(1973).

Resolution of a 9 -hydroxy racemate (the component enantiomers areillustrated by LVIII and LIX below) may be accomplished by conversion ofthe racemate, wherein the C₁₁ and C₁₅ or C₁₆ hydroxy functions have beenpreferentially blocked by trialkylsilyl groups, (for example, by firstderivatizing the two hydroxy functions in the corresponding 9-oxoderivative and then reducing the 9-carbonyl as described hereinabove),to the corresponding phthalate half acid-ester, deblocking the C₁₁ andC₁₅ hydroxy functions and conversion of the diacid (e.g., LX) to amixture of diastereomeric bis salts (e.g., LXI) with an optically activeamine (e.g., 1-(-)-α-methylbenzylamine, D-(+)-α-methylbenzylamine,brucine, dehydroabietylamine, strychnine, quinine, cinchonine,cinchonidine, quinidine, ephedrine, deoxyephedrine, amphetamine,(+)-2-amino-1-butanol, (-)-2-amino-1-butanol and the like). Theresulting diastereomers are then separated by fractional crystallizationand the individual components are then converted by acidification andsaponification to the individual optically active parent 9α-hydroxyenantiomers (LVIII) and (LIX), oxidation of which, after preferentialblocking of the C₁₁ and C₁₅ hydroxy functions with tetrahydropyranyl ortrialkylsilyl groups, provides, after deblocking, the correspondingindividual 9-oxo-enantiomers (LXII) and (LXIII). If necessary, the 11-and 15-hydroxy groups can be converted to tetrahydropyranyloxy groupsprior to saponification of the phthalate ester. (For an appropriateliterature procedure see E. W. Yankee, C. H. Lin and J. Fried, Journ.Chem. Soc., 1972, 1120). ##STR22##

Another procedure involves conversion of the 9α-hydroxy racemate (as theprostenoic acid ester and with the C₁₁ and C₁₅ alcohol functionspreferentially blocked as trialkylsilyl ethers) to the diastereomericcarbamates with an optically active isocyanate, e.g.,(+)-1-phenylethylisocyanate or (-)-1-phenylethylisocyanate, followed bydeblocking. Separation of the resulting diastereomers, for example(LXIV) and (LXV), can be accomplished by fractional cyrstallization orby the usual chromatographic procedures, or if necessary by high speedliquid chromatography involving, recycling techniques. Base-treatment ofthe individual diastereomeric carbamates affords the individualdiastereomeric alcohols, for example (LVIII) and (LXVI). ##STR23##

It is also possible to effect resolution of the 9α-hydroxy racemate,preferably as the prostenoate ester, by esterification of the 9α-hydroxyfunction (prior preferential blocking as discussed hereinabove of C₁₁and C₁₅ or C₁₆ hydroxy functions as tetrahydropyranyl or trialkylsilylethers) with an optically active acid, via its acid chloride followed bydeblocking the C₁₁ and C₁₅ or C₁₆ alcohol groups. Suitable opticallyactive acids include -camphoric acid, menthoxyacetic acid, 3α-acetoxy-Δ⁵-etianic acid, (-)-α-methoxy-α-α-trifluoromethylphenylacetic acid and(+)-α-methoxy-α-trifluoromethylphenylacetic acid, and the like. Theresulting diastereomeric esters, for example, (LXVII) and (LXVIII), arethen separated by fractional crystallization or by chromatographictechniques including, if necessary, the use of high speed liquidchromatography. Saponification of the individual diastereomers thenprovides the individual 9α-hydroxy-rostenoic acid enantiomers (LVIII)and (LXVI). ##STR24##

Dehydration as described above, of the optically active PGE compoundsthen furnishes the PGA compounds in their optically active forms.Treatment of the optically active PGE compounds with base as describedabove, furnishes the corresponding optically active PGB compounds. Theoptically active 11-cyano derivatives are formed by the reaction of theoptically active PGA compounds with acetone cyanohydrin as describedabove.

The preparation of the requisite cyclopentenones which contain a sulfuratom in the α-chain is described in Flowsheet C. In accordance withFlowsheet C wherein t is hereinabove described, treatment of2-furyllithium (LXXIII) with a ω-chloroaldehyde (LXXIV) provides thechlorolcohol (LXXV). Treatment of the chloroalcohol (LXXV) withethylmercaptoacetate furnishes the hydroxy ester (LXXVI) which uponhydrolysis with sodium formate/formic acid provides the3-hydroxy-cyclopentenone (LXXVII). Treatment of the cyclopentenone(LXXVII) with sulfuric acid provides the required4-hydroxy-cyclopentenone (LXXVIII) which after treatment withchlorotrimethylsilane and hexamethyl disilazene in pyridine provides thebissilylated cyclopentenone (LXXIX).

The 3-hydroxy-cyclopentenones of the type (LXXVII), the4-hydroxy-cyclopentenones of the type (LXXXVIII), and the bissilylatedor bistetrahydropyrayl protected or other suitably protected4-hydroxy-cyclopentenone of the type (LXXIX) are novel and usefulcompounds which are also embraced by this invention, as are the novelintermediates required for their preparation. ##STR25##

The ring system of certain of the novel compounds of this inventionallow them to be characterized as follows: ##STR26##

The novel compounds of this invention possess the pharmacologicalactivity described below as associated with the appropriateabove-described prostaglandin type.

The known PGA and PGB compounds are all potent in causing multiplebiological responses even at low doses. Moreover, for many applications,these known prostaglandins have an inconveniently short duration ofbiological activity. In striking contrast, the novel prostaglandinanalogs of this invention are substantially more specific with regard topotency in causing prostaglandin-like biological responses, and/orhaving a substantially, longer duration of biological activity.Therefore, each of these novel prostaglandin analogs is surprisingly andunexpectedly more useful than one of the corresponding above-mentionedknown prostaglandins for at least one of the pharmacological purposesindicated below for the latter, either because it has a different andnarrower spectrum of biological activity then the known prostaglandins,and therefore is more specific in its activity and causes smaller andfewer undesired side effects than the known prostaglandins, or becauseof its prolonged activity, fewer and smaller doses of the novelprostaglandin analog can frequently be used to attain the desiredresult.

Another advantage of the novel compounds of this invention, comparedwith the known prostaglandins, is that these novel compounds areadministered effectively, orally, sublingually, intravaginally, bucally,or rectally, in addition to the usual intravenous, intramuscular, orsubcutaneous injection or infusion methods indicated above for the usesof the known prostaglandins. These qualities are advantageous becausethey facilitate maintaining uniform levels of these compounds in thebody with fewer, shorter, or smaller doses, and make possibleself-administration by the patient.

PGA and PGB compounds, and their esters and pharmacologically acceptablesalts, are extremely potent in causing various biological responses. Forthat reason, these compounds are useful for pharmacological purposes.See, for example, Bergstrom, et al., Pharmacol. Rev., 20, 1 (1968), andreferences cited therein. A few of those biological responses aresystemic arterial blood pressure lowering in the case of the PGAcompounds as measured, for example, in anesthetized (phenobarbitalsodium) pentolinium-treated rats with indwelling aortic and right heartcannulas; stimulation of smooth muscle as shown, for example by tests onstrips of guinea pig ileum, rabbit duodenum, or gerbil colon;potentiation of other smooth muscle stimulants; antilipolytic activityas shown by antagonism of epineephrine-induced mobilization of freefatty acids or inhibition of the spontaneous release of glycerol fromisolated rat fat pads; inhibition of gastric secretion in the case ofthe PGA compounds as shown in dogs with secretion stimulated by food orhistamine infusion; activity on the central nervous system; and in thecase of PGB compounds, stimulation of epidermal proliferation andkeratinization as shown when applied in culture to embryonic chick andrat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdisease and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

The PGA compounds are useful in mammals, including man and certainuseful animals, e.g., dogs and pigs, to reduce and control excessivegastric secretion, thereby reducing or avoiding gastric erosion orgastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 μg to about 500 μgper kg. of body weight per minute, or in a total daily dose by injectionor infusion in the range about 0.1 to about 20 mg. per kg. of bodyweight per day, the exact dose depending on the age, weight, andcondition of the patient or animal, and on the frequency and route ofadministration. These compounds may also be useful in conjunction withvarious non-steroidal anti-inflammatory agents, such as aspirin,phenylbutazone, indomethacin and the like, to minimize the well-knownulcerogenic effects of the latter.

The PGA compounds are useful as hypotensive agents to reduce bloodpressure in mammals including man. For this purpose, the compounds areadministered by intravenous infusion at the rate about 0.01 to about 50μg per kg of body weight per minute, or in a single or multiple doses ofabout 25 to 2500 μg per kg. of body weight total per day.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal disfunction, especially in cases of severelyimpaired renal blood flow, for example, the hepatorena syndrome andearly kidney transplant rejection. In case of excessive or inappropriateADH (antidiuretic hormone vasopressin) secretion, the diuretic effect ofthese compounds is even greater. In anephretic states, the vasopressinaction of these compounds is especially useful. For that reason, thesecompounds are useful to promote and accelerate healing of skin which hasbeen damaged, for example, by burns, wounds, and abrasions, and aftersurgery. These compounds are also useful to promote and accelerateadherence and growth of skin autografts, especially small, deep (Davis)grafts which are intended to cover skinless areas by subsequent outwardgrowth rather than initially, and to retard rejection of homografts.

For these purposes, these compounds are preferably adminstered topicallyat or near the site where call growth and keratin formation is desired,advantageously as an aerosol liquid or micronized powder spray, as anisotonic aqueous solution in the case of wet dressing, or as a lotion,cream, or ointment in combination with the usual pharmaceuticallyacceptable diluents. In some instances, for example, when there issubstantial fluid loss as in the case of extensive burns or skin lossdue to other causes, systemic administration is advantageous, forexample, by intravenous injection or infusion, separate or incombination with the usual infusions of blood, plasma, or substitutesthereof. Alternative routes of administration are subcutaneous orintramuscular near the site, oral, sublingual, buccal, rectal, orvaginal. The exact dose depends on such factors as the route ofadministration, and the age, weight, and condition of the subject. Toillustrate a wet dressing for topical application to second and/or thirddegree burns of skin area 5 to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containingone to 500 μg/ml of the PGB compound or several times that concentrationof the PGE compound. Especially for topical use, these prostaglandinsare useful in combination with antibiotics, for example, gentamycin,neomycin, polymyxin B, bacitracin, spectinomycin, and oxytetracycline,with other antibacterials, for example, mafenide hydrochloride,sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoidsteroids, for example hydrocortisone, prednisolone, methylprednisolone,and fluprednisolone, each of those being used in the combination at theusual concentration suitable for its use alone.

The novel compounds of this invention induce the biological responsesdescribed hereinabove as associated with its particular prostaglandintype. These novel compounds are accordingly useful for theabove-described corresponding purposes in the same manner as describedabove.

The novel PGA compounds of this invention are also useful asbronchodilators for the treatment of asthma and chronic bronchitis; assuch they may be conveniently administered by inhalation of aerosolsprays prepared in a dose range of about 10 μg to about 10 mg. per ml.of a pharmacologically suitable liquid vehicle.

These derivatives described hereinabove are also more selective in theirbiological action and induce a more prolonged effect than thecorresponding natural prostaglandins. These preparations are novel,completely unanticipated and provide distinct and important advantages.

In addition, certain of the novel compounds of this invention are usefulfor the preparation of other novel compounds of this invention.

It is well known that platelet aggregation inhibitors may be useful asanti-thrombotic drugs. Inhibition of platelet aggregation can beconveniently measured in vitro by monitoring changes in optical densityand/or light transmission in platelet rich plasma upon addition ofsuitable aggregating agents such as adenosine diphosphate, epinephrine,thrombin or collagen. Alternatively, platelet aggregation can bemeasured in vitro using platelet rich plasma obtained at various timeintervals from animals given inhibitors by an oral or parenteral route.

The compounds of the present invention exhibit the ability to inhibitplatelet aggregation in vitro when tested by the following procedure.

Human protein rich plasma is incubated with modified Tyrode's solutionin a proportion of 40-50% human protein rich plasma. The test compoundsare added at varying concentrations and after 5 minutes incubation, anaggregating agent such as adenosine diphosphate or collagen is added.The change in optical density (light transmission) is monitored by eyeand inhibition is recorded as a (-) or lack of inhibition is recorded asa (+). Test compounds are considered active if they inhibit adenosinediphosphate or collagen induced aggregation at a concentration of 25mcg/ml or less within 5-10 minutes. The results of this test onrepresentative compounds of this invention appear in Table A.

                                      TABLE A                                     __________________________________________________________________________    Inhibition of Platelet Aggregation - In Vitro                                                          Adenosine Diphosphate                                                                       Collagen                                                        Drug Concentration μg/ml                                                                  Drug Concentration μg/ml             Compound               250 25 2.5 0.25                                                                             250 25 2.5 0.25                        __________________________________________________________________________    nat(and ent)-15-Hydroxy-9-oxo-15,16-tetramethylene-                           17,18,19,20-tetranor-13-trans,5-cis,10-prostatrie-                                                     (-) (+)       (-) (+)                                noic acid                                                                     nat(and ent)-9α/β-Cyano,15-hydroxy-9-oxo-15,16-                    tetramethylene-17,18,19,20-tetranor-5-cis-13-                                                          (-) (-)                                                                              (-)    (-) (-)                                trans-prostadienoic acid                                                      __________________________________________________________________________     (-) = Inhibition                                                              (+) = No inhibition                                                      

The compounds of this invention are also useful as bronchodilators andaccordingly have potential application in the treatment of asthma.

Bronchodilator activity is determined in guinea pigs againstbronchospasms elicited by intravenous injections of 5-hydroxytryptamine,histamine or acetylcholine by the Konzett procedure. [See J. Lulling, P.Lievens, F. El Sayed and J. Prignot, Arzeneimittel-Forschung, 18, 995(1968).] In Table B bronchodilator activity for representative compoundsof this invention against one or more of the three spasmogenic agents isexpressed as an ED₅₀ determined from the results obtained with threelogarithmic cumulative intravenous doses.

                                      TABLE B                                     __________________________________________________________________________    Bronchodilator Activity                                                                                ED.sub.50, mg/kg                                       Compound               5-Hydroxytryptamine                                                                      Histamine                                                                           Acetylcholine                       __________________________________________________________________________    nat(and ent)-9α/β-Cyano,15-hydroxy-9-oxo-15,16-                    tetramethylene-17,18,19,20-tetranor-5-cis-13-                                                           1.81 × 10.sup.-3                                                                  367 × 10.sup.-6                                                                2.74 × 10.sup.-3             trans-prostadienoic acid                                                      nat(and ent)-15-Hydroxy-9-oxo-15,16-tetramethylene-                           17,18,19,20-tetranor-13-trans,5-cis,10-prostatrie-                                                     >3.2 × 10.sup.-3                                                                   632 × 10.sup.-6                                                               >3.2 × 10.sup.-3              noic acid                                                                     __________________________________________________________________________

The invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 Preparation oftrans-1-Hydroxy-2-(3-trifluoromethyl)phenoxycyclopentane

A mixture of 88 g of cyclopentene oxide, 150.7 g of3-trifluoromethylphenol, 5.0 g of sodium hydroxide in 30 ml of water and4.0 g of methyltricaprylyl ammonium chloride is stirred at 70°-80° C.for 51 hours and at 25° C. for 96 hours. The mixture is then dilutedwith methylene chloride and poured into water. The organic layer iswashed with dilute sodium hydroxide solution and water. The solution isdried over magnesium sulfate. The solvent is removed giving 221.5 g of aliquid which is distilled (bp 110°-113° C. 0.8 mm) givingtrans-1-hydroxy-2-(3-trifluoromethyl)phenoxycyclopentane.

EXAMPLE 2

In the manner described above in Example 1 from 4-fluorophenol andcyclopentane epoxide is preparedtrans-1-hydroxy-2-(4-fluoro)phenoxycyclopentane.

EXAMPLE 3

In the manner described above in Example 1 from 3-chlorophenol andcyclopentane epoxide is preparedtrans-1-hydroxy-2-(3-chloro)phenoxycyclopentane.

EXAMPLE 4 Preparation of 2-(3-Trifluoromethylphenoxy)cyclopentanone

To a suspension of 327.43 g of pyridinium chlorochromate in one liter ofmethylene chloride is added 220 g oftrans-1-hydroxy-2-(3-trifluoromethylphenoxy)cyclopentane in 500 ml ofmethylene chloride. The mixture is stirred for 2 hours 15 minutes.Another 50 g of the oxidizing agent is added and the mixture is stirredfor 41/2 hours. The mixture is diluted with ether and decanted from ablack residue which is washed with more ether. The combined solutionsare filtered through silica gel. The solvent is removed. The residue isdissolved in ether and again filtered through silica-gel. The solvent isremoved and the residue is distilled (bp 113°-116° C., 1.5 mm) to give188 g of 2-(3-trifluoromethylphenoxy)cyclopentanone.

EXAMPLE 5

In the manner described above for Example 4 is prepared from the productof Example 2; 2-(4-fluorophenoxy)cyclopentanone.

EXAMPLE 6

In the manner described above for Example 4 is prepared from the productof Example 3; 2-(3-chlorophenoxy)cyclopentanone.

EXAMPLE 7 Preparation of 1R,2S(and1S,2R)-1-Ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane

Into 150 ml of dry tetrahydrofuran is bubbled purified acetylene, as asolution of 2.4M n-butyl magnesium chloride (92 ml) is added dropwisewith stirring over a 2 hour period. To the resulting solution ofacetylene magnesium chloride is added 21 g of 2-butylcyclopentanone in50 ml of tetrahydrofuran dropwise over 15 minutes. The solution isstirred for 30 minutes and then is poured into an ice cold solution ofsaturated ammonium chloride. The mixture is acidified to pH 5 andextracted with ether. The ether solution is washed with brine and driedover magnesium chloride. The ether is removed and the residue isdistilled giving 14.8 g of a colorless liquid. This is chromatographedon a dry column of silica-gel eluting with benzene-ethyl acetate (19:1)to separate isomers giving 1R,2S(and1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane.

EXAMPLE 8 Preparation of 1-propargyl-1-hydroxycyclohexane

A stirred suspension of 121.6 g (5.0 mol) of magnesium in 1-l ofanhydrous ether is treated with 0.6 g of mercuric chloride and about 100mg of iodine. After several minutes, 3 ml of propargyl bromide is addedand if no exotherm is noted, a small amount of reacting propargylbromide and magnesium in ether is added. When the reaction begins, amixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargylbromide is added dropwise at a rate that produces vigorous refluxing ofthe solution. (The propargyl bromide must always be present in someexcess otherwise the reaction will stop. If this happens, the additionof about 1 ml of propargyl bromide will restart the reaction.) Afterabout half of the propargy bromide-cyclohexanone mixture has been added,another 500-750 ml of ether is used to dilute the reaction mixture. Atthe end of the addition, the reaction mixture is refluxed for at least0.5 hour, cooled and poured into 4 liters of saturated ammonium chlorideduring good stirring. The ethereal layer is separated and the aqueouslayer is washed with ether several times and the combined extract iswashed twice with saturated sodium chloride solution and dried overanhydrous magnesium sulfate. Evaporation of the ether yields 583 g (630g theory) of a dark oil which is distilled giving purified1-propargyl-1-hydroxycyclohexane.

EXAMPLES 9-27

In the manner of Examples 7 and 8 described above the followingacetylenic alcohols listed in Table I were prepared from the acetylenicGrignard reagent and ketone specified.

                                      Table I                                     __________________________________________________________________________    Example                                                                            Grignard Reagent                                                                       Ketone      Acetylenic Alcohol                                  __________________________________________________________________________     9   acetylene magne-                                                                       cyclohexanone                                                                             1-ethynyl-1-hydroxycyclohexane                           sium chloride                                                            10   acetylene magne-                                                                       cyclopentanone                                                                            1-ethynyl-1-hydroxycyclopentane                          sium chloride                                                            11   acetylene magne-                                                                       cycloheptanone                                                                            1-ethynyl-1-hydroxycycloheptane                          sium chloride                                                            12   acetylene magne-                                                                       3-propylcyclopentanone                                                                    1R,3S-(and 1S,3R-) 1-ethynyl-1-hydroxy-                  sium chloride        3-propylcyclopentane                                13   acetylene magne-                                                                       3-propylcyclopentanone                                                                    1R,3R-(and 1S,3S-) 1-ethynyl-1-hydroxy-                  sium chloride        3-propylcyclopentane                                14   acetylene magne-                                                                       2-butylcyclohexanone                                                                      1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride        2-butylcyclohexane                                  15   acetylene magne-                                                                       2-butylcyclohexanone                                                                      1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride        2-butylcyclohexane                                  16   acetylene magne-                                                                       2-(3-trifluoro-                                                                           1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          methylphenoxy)-                                                                           2-(3-trifluoromethylphenoxy)cyclopen-                             cyclopentanone                                                                            tane                                                17   acetylene magne-                                                                       2-(3-trifluoro-                                                                           1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          methylphenoxy)-                                                                           2-(3-trifluoromethylphenoxy)cyclopentane                          cyclopentanone                                                  18   acetylene magne-                                                                       2-(4-fluorophen-                                                                          1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          oxy)cyclopentanone                                                                        2-(4-fluorophenoxy)cyclopentane                     19   acetylene magne-                                                                       2-(4-fluorophen-                                                                          1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          oxy)cyclopentanone                                                                        2-(4-fluorophenoxy)cyclopentane                     20   acetylene magne-                                                                       2-(3-chlorophenoxy)-                                                                      1R,2S-(and 1S,2R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          cyclopentanone                                                                            2-(3-chlorophenoxy)cyclopentane                     21   acetylene magne-                                                                       2-(3-chlorophenoxy)-                                                                      1R,2R-(and 1S,2S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          cyclopentanone                                                                            2-(3-chlorophenoxy)cyclopentane                     22   acetylene magne-                                                                       3-methylcyclohexa-                                                                        1R,3S-(and 1S,3R-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          none        3-methylcyclohexane                                 23   acetylene magne-                                                                       3-methylcyclohexa-                                                                        1R,3R-(and 1S,3S-) 1-ethynyl-1-hydroxy-                  sium chloride                                                                          none        3-methylcyclohexane                                 24   propargyl magne-                                                                       2-butylcyclopenta-                                                                        1R,2S-(and 1S,2R-) 1-propargyl-1-hydroxy-                sium bromide                                                                           none        2-butylcyclopentane                                 25   propargyl magne-                                                                       2-butylcyclopenta-                                                                        1R,2R-(and 1S,2S-) 1-propargyl-1-hydroxy-                sium bromide                                                                           none        2-butylcyclopentane                                 26   propargyl magne-                                                                       2-(3-trifluoro-                                                                           1R,2S-(and 1S,2R-) 1-propargyl-1-hydroxy-                sium bromide                                                                           methylphenoxy)-                                                                           2-(3-trifluoromethylphenoxy)cyclopentene                          cyclopentanone                                                  27   propargyl magne-                                                                       2-(3-trifluoro-                                                                           1R,2R-(and 1S,2S)-1-propargyl-1-hydroxy-                 sium bromide                                                                           methylphenoxy)-                                                                           2-(3-trifluoromethylphenoxy)cyclopenta-                           cyclopentanone                                                                            nane                                                __________________________________________________________________________

EXAMPLE 28a Preparation of 1R,2S(and1S,2R)-1-Ethynyl-1-trimethylsilyloxy-2-butylcyclopentane

To a solution of 29.4 g of 1R,2S(and1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 30.2 g of imidazolein 180 ml of dimethylformamide is added at 0° C. with stirring 24.1 g oftrimethylsilylchloride. The mixture is stirred for 3 hours. The mixtureis poured into 700 ml of hexane and washed twice with water and oncewith brine. The ether solution is dried over magnesium sulfate. Thesolvent is removed and the residue is distilled (bp 64°-72° C., 0.6 mm)to give 35.8 g of 1R,2S(and1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane.

EXAMPLE 28b Preparation of 1R,2R(and1S,2S)-1-Ethynyl-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 45.0 g of 1R,2R(and1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 46.2 g of imidazolein 255 ml of dimethylformamide at 0° C. under nitrogen is added 36.9 gof trimethylsilylchloride. The mixture is stirred at room temperaturefor 3 hours and then poured into 700 ml of hexane. Water is added, theorganic layer is separated and the water layer is extracted with hexane.The combined hexane solutions are washed twice with water and dried overmagnesium sulfate. The solvent is removed and the residue is distilledgiving the product as 53 g of a colorless oil.

EXAMPLE 28c Preparation of 1-Ethynyl-1-trimethylsilyloxycyclohexane

A 194 g portion of imidazole and 158.2 g of 1-ethynylcyclohexan-1-ol aremixed with 500 g of dimethylformamide with cooling in an ice bath. A 152g portion of trimethylchlorosilane is added with cooling and stirring inabout one minute. The mixture is stirred for one hour and allowed tostand overnight. One liter of hexane is added. The lower layer isseparated, diluted with water and extracted with hexane. The hexanelayers are washed several times with water and then combined and driedover magnesium sulfate. Filtration and then evaporation of the hexanegives 198.5 g of product which is distilled giving 168 g of the desiredproduct.

EXAMPLE 28D Preparation of 1-Propargyl-1-trimethylsilyloxycyclohexane

To a stirred solution of 55.4 g of 1-(2-propyn-1- -yl) cyclohexanol [H.Gutmann, et al., Helv. Chim. Acta, 42, 719 (1959)] and 79 g of imidazolein 240 ml of DMF at 10° C. initially is added 56 ml ofchlorodimethylsilane during 10 minutes. The cloudy yellow solution isstirred at room temperature for 26 hours. The resulting mixture ispartitioned between 1000 ml of hexane and 400 ml of water at 0°-5° C.The hexane phase is washed successively with 6×200 ml of cold water and200 ml of brine. The extract is dried over magnesium sulfate, filtered,and evaporated to give 85 g of colorless liquid, i.r. (film):1240 and830 cm⁻¹ (trimethylsilyloxy group).

EXAMPLE 29A Preparation of 1R,2S(and 1S,2R)-1-(trans-2-Iodovinyl)-1-tri- methylsilyloxy-2-butylcyclopentane

To a mixture of 9.2 g of sodium borohydride and 45.8 g of2-methyl-2-butene in 350 ml of dry tetrahydrofuran at 0° C. withstirring under nitrogen is added, over 20 minutes, 41.1 ml of borontrifluoride etherate. After 3 hours, to this resulting solution ofdiisoamylborane is added 38.8 g of 1R, 2S (and 1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane in 40 ml oftetrahydrofuran in 20 minutes. The mixture is stirred 2 hours and thenstored at -20° C. overnight. The mixture is allowed to warm to 0° C. andat 0° C. 85 g of dry trimethylamineoxide is added portionwise over 20minutes. After stirring at 25° C. for one hour, the mixture is filteredthrough diatomaceous earth. The filtrate is poured simultaneously with asolution of 230 g of iodine in 250 ml of tetrahydrofuran into a stirred,cold solution of 430 g of sodium hydroxide in 1900 ml of water. Afterstirring for 30 minutes, the organic layer is separated. The aqueouslayer is extracted with ether. The combined organic solutions are washedtwice with a saturated solution of sodium thiosulfate and once withbrine. The solution is dried over magnesium sulfate, the solvent isremoved and the residue is dissolved in hexane. The hexane solution isfiltered through diatomaceous earth and silica gel. The hexane isremoved and the residue is purified by dry column chromatography onsilica gel eluting with hexane: 45.35 g of 1R,2S(and1S,2R)-1-(trans-2-iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane isobtained.

EXAMPLE 29B Preparation of 1R,2R(and 1S,2S)-1-(trans-2-Iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 12.22 g of sodium borohydride and 60.82 g of2-methyl-2-butene in 450 ml of tetrahydrofuran under nitrogen at 0° C.,is added 54.6 ml of boron trifluoride etherate, dropwise over a 20minute period. The solution is stirred at 0° C. for 2 hours and then atroom temperature for 30 minutes. This solution is cooled to 0° C. and55.5 g of 1R,2R(and1S,2S)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane in 50 ml oftetrahydrofuran is added. The mixture is allowed to stand in a cold roomovernight. To this mixture at 0° C. is added with stirring 112.8 g oftrimethylamine oxide over a 20 minute period. The mixture is stirred atroom temperature for 90 minutes and then filtered. To the filtrate isadded simultaneously a solution of 565 g of sodium hydroxide in 2000 mlof water and a solution of 300 g of iodine in 300 ml of tetrahydrofuran.The mixture is stirred 30 minutes, the organic layer is separated andthe aqueous layer is extracted with ether. The combined organicsolutions are washed with saturated sodium thiosulfate solution and withsaturated sodium chloride solution. The solution is dried with magnesiumsulfate and filtered through a pad of silica gel. The solution isremoved giving an orange liquid which is chromatographed on a dry columnof silica gel giving 59.5 g of the product as a yellow liquid.

EXAMPLE 30 Preparation of2-(3-Tri-n-butylstannyl-2-trans-propenyl)-1-trimethylsilyloxycyclohexane

To a stirred mixture of 31/5 g of1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg ofazobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. Thestirred mixture is heated to about 80° C. The initial exothermicreaction is moderated, and the temperature is subsequently maintained at130°-135° C. for one hour.

The product is distilled to afford 56 g of colorless liquid, bp150°-160° C. (0.15-0.3 mm), pmr (CDCl₃): 6.0 (multiplet, vinyl protons).

EXAMPLES 31-50

Using the procedure outlined above for Examples 28a, b, c and d, theacetylenic alcohols listed in Table II are converted to theircorresponding acetylenic trimethylsilyloxy derivatives; these in turnusing the procedure outlined above for Examples 29a and 29b, wereconverted to their corresponding trans-2-iodovinyl derivatives or usingthe procedure out above for Example 30, were converted to theircorresponding trans-2-tri-n-butylstannyl derivatives (Table II).

                                      Table II                                    __________________________________________________________________________    Example                                                                            Acetylene of Example                                                                     Method of Example                                                                       Vinyl Iodide or Vinyl Tin Compound                  __________________________________________________________________________    31    9         29        1-(trans-2-iodovinyl)-1-trimethylsilyloxy-                                    cyclohexane                                         32   10         29        1-(trans-2-iodovinyl)-1-trimethylsilyloxy-                                    cyclopentane                                        33   11         30        1-(trans-2-tri-n-butylstannylvinyl)-1-tri-                                    methylsilyloxycycloheptane                          34   12         29        1R,3S-(and 1S,3R-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-3-propylcyclopentane              35   13         29        1R,3R-(and 1S,3S-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-3-propylcyclopentane              36    7         29        1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-2-butylcyclopentane               37   14         29        1R,2S-(and 1S,2R-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-2-butylcyclohexane                38   15         29        1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-2-butylcyclohexane                39   16         30        1R,2S-(and 1S,2R-) 1-(trans-2-tri-n-butyl-                                    stannylvinyl)-1-trimethylsilyloxy)-2-(3-                                      trifluoromethylphenoxy)cyclopentane                 40   17         30        1R,2R-(and 1S,2S-) 1-(trans-2-tri-n-butyl-                                    stannylvinyl)-1-trimethylsilyloxy-2-(3-tri-                                   fluoromethylphenoxy)cyclopentane                    41   18         29        1R,2S-(and 1S,2R-) 1-(trans-2-iodovinyl)-                                     1-trimethylsilyloxy-2-(4-fluorophenoxy)-                                      cyclopentane                                        42   19         29        1R,2R-(and 1S,2S-) 1-(trans-2-iodovinyl)-                                     1-trimethylsilyloxy-2-(4-fluorophenoxy)-                                      cyclopentane                                        43   20         30        1R,2S-(and 1S,2R-) 1-(trans-2-tri-n-butyl-                                    stannylvinyl)-1-trimethylsilyloxy-2-(3-                                       chlorophenoxy)cyclopentane                          44   21         30        1R,2R-(and 1S,2S-) 1-(trans-2-tri-n-butyl-                                    stannylvinyl)-1-trimethylsilyloxy-2-(3-                                       chlorophenoxy)cyclopentane                          45   22         29        1R,3S-(and 1S,3R-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-3-methylcyclohexane               46   23         29        1R,3R-(and 1S,3S-) 1-(trans-2-iodovinyl)-1-                                   trimethylsilyloxy-3-methylcyclohexane               47   24         30        1R,2S-(and 1S,2R-) 1-(3-tri-n-butylstannyl-                                   2-trans-propenyl)-1-trimethylsilyloxy-2-                                      butylcyclopentane                                   48   25         30        1R,2R-(and 1S,2S-) 1-(3-tri-n-butylstannyl-                                   2-trans-propenyl)-1-trimethylsilyloxy-2-                                      butylcyclopentane                                   49   26         30        1R,2S-(and 1S,2R-) 1-(3-tri-n-butylstannyl-                                   2-trans-propenyl)-1-trimethylsilyloxy-2-                                      (3-trifluoromethylphenoxy)cyclopentane              50   27         30        1R,2R-(and 1S,2S-) 1-(3-tri-n-butylstannyl-                                   2-trans-propenyl)-1-trimethylsilyloxy-2-                                      (3-trifluoromethylphenoxy)cyclopentane              __________________________________________________________________________

EXAMPLE 51 Preparation of2-(6-Carbotrimethylsilyloxhex-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one

To a solution of one g of2-(6-carboxyhex-2-cis-enyl)-4-hydroxycyclopent-2-en-1-one in 12.5 ml ofdry pyridine at 15° C. under argon is added with stirring 3.3 ml ofhexamethyldisilazane (HMDS) followed by dropwise addition of 1.6 ml oftrimethylchlorosilane (TMCS). The resulting mixture is stirred atambient temperature for one hour then taken to dryness (vac. pump). Theresidue is taken up in hexanes and filtered thru Celite. Evaporation ofthe mother liquor followed by two evaporations with toluene furnished1.5 g (96%) of pure2-(6-carbotrimethylsilyloxyhex-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one.

EXAMPLE 52 Preparation of2-(6-Carbotrimethylsilyloxyhexyl)-4-trimethylsilyloxycyclopent-2-en-1-one

To a solution of one g of2-(6-carboxyhexyl)-4-hydroxycyclopent-2-en-1-one in 12.5 ml of drypyridine at 15° C. under argon, is added with stirring 3.3 ml ofhexamethyl disilazane followed by dropwise addition of 1.6 ml oftrimethylchlorosilane. The resulting mixture is stirred at ambienttemperature for one hour and then taken to dryness. The residue is takenup in hexane and filtered through diatomaceous earth. Evaporation of themother liquor followed by two evaporations with toluene gives pureproduct.

EXAMPLE 53 Preparation of2-(6-carbomethoxhexyl)-4(R)-trimethylsilyoxycyclopent-2-en-1-one

To a solution of 1.0 g of2-(6-carbomethylhexyl)-4(R)-hydroxycyclopent-2-en-1-one [R. Pappo, etal., Tetrahedron Letters, 943 (1973)] in 12.5 ml of dry pyridine at 15°under argon was added with stirring 3.3 ml (24 moles) ofhexamethyldisilazone (HMDS) followed by dropwise addition of 1.6 ml(20.5 moles) of trimethylchlorosilane (TMCS). The resulting mixture wasstirred at ambient temperature for 1 hour then taken to dryness (vac.pump). The residue is taken up in hexanes and filtered thru Celite.Evaporation of the mother liquid followed by two evaporations withtoluene furnished pure2-(6-carbomethoxyhexyl)-4(R)-trimethylsilyloxyhexyl)-4(R)-trimethylsilyloxycyclopent-2-en-1-one.

EXAMPLE 54 Preparation of2-(6-carbomethoxyhexyl)-4(S)-trimethylsilyloxycyclopent-2-en-1-one

In the manner described in Example 53 treatment of2-(6-carbomethoxyhexyl)-4(S)-hydroxycyclopent-2-en-1-one [R.Pappo, etal., Tetrahedron Letters, 943 (1973)] with hexamethyldisilazane andtrimethylsilylchloride gives the subject product.

EXAMPLE 55 Preparation of 5-chloro-1-(2-furyl)-1-pentanol

To a stirred suspension of 2-furyllithium (prepared from 0.53 moles ofn-butyllithium and 39.5 g of furan by the procedure of J. Org. Chem.,27, 1216 (1962) in 350 ml of ether and ca. 200 ml of hexane at -78° isadded a solution of 57.9 g of 5-chloropentanol (Chem. Abstr., 59. 7579F(1963)) in 80 ml of ether during 25 minutes. The mixture is warmed to0°during 20 minutes, stirred at 0° for 15 minutes, and treated with 140ml of saturated ammonium chloride. The ether phase is washed with waterand brine, dried over magnesium sulfate and potassium carbonate mixture,and concentrated to give a liquid, pmr spectrum (CDCl₃): δ 3.59(triplet, CH₂ Cl₂) and 4.70 (triplet, CH₂ CHOH).

Example 56 Preparation of5-(carbethoxymethylthio)-1-(2-furyl)-1-pentanol

To a stirred, refluxing mixture of 76 g of ethyl mercaptoacetate, 79.5 gof 5-chloro-1-(2-furyl)-1-pentanol and 10 ml of 1.5M sodium ethoxide inethanol is added an additional 300 ml of 1.5m sodium ethoxide during 15minutes. The resulting mixture is stirred at reflux for 3 hours, cooled,and concentrated to remove most of the ethanol. The residue ispartitioned with ether and water. The ether phase is washed with brineand dried over potassium carbonate. The solution is concentrated,diluted with xylene, and again concentrated to give an oil, pmr spectrum(CDCl₃): δ 3.24 (singlet, --S--CH₂ CO₂ C₂ H₅) and 4.70 (triplet, CH₂CHOH).

EXAMPLE 57 Preparation of2-(6-carboxy-5-thiahexyl)-4-hydroxycyclopent-2-en-1-one

A stirred solution of 125 g of5-(carbethoxymethylthio)-1-(2-furyl)-1-pentanol, 22.4 g of sodiumformate, 250 ml of dioxane and 1330 ml of water is refluxed for 20hours.

The solution, containing crude3-hydroxy-2-[4-(carbethoxymethylthio)butyl]cyclopent-4-en-1-one, iscooled and treated during 10 minutes with 75 ml. of sulfuric acid(d═1.84) with stirring. The stirred solution is refluxed for 16 hours,cooled, saturated with sodium chloride, and extracted with ethylacetate. The extract is washed with brine, dried over magnesium sulfate,and concentrated. The residue is subjected to chromatography on silicagel with chloroform progressively enriched in ether, ether, and etherprogressively enriched in acetone to afford the subject compound as anoil, pmr spectrum (CDCl₃): δ3.24 (singlet, --S--CH₂ --CO₂ C₂ H₅), 5.0(broad singlet --CHOH--).

EXAMPLE 58 Preparation of2-(6-carbotrimethylsilyloxy-5-thiahexyl)-4-trimethylsiloxycyclopent-2-en-1-one

To a stirred solution of 28.4 g of4-hydroxy-2-[4-(carboxymethylthio)butyl9 cyclopent-2-3n-1-one and 76 mlof hexamethyldisilazane in 330 ml of pyridine at 5° C. is added 38 ml ofchlorotrimethylsilane during 5 minutes. The mixture is stirred atambient temperature for 3.5 hours, at 45° C. for 5 minutes, and thenevaporated to remove solvent. The residue is stirred with 1000 ml ofpetroleum ether and filtered. The filtrate is treated with charcoal andfiltered; this filtrate is concentrated with the aid of toluene to givea liquid, pmr spectrum (CDCl₃): 0.18 (singlet, trimethylsiloxy group)and 0.28 (singlet, trimethylsiloxycarbonyl group).

EXAMPLE 59 Preparation of 4-chloro-1-(2-furyl)-1-butanol

To a stirred suspension of 2-furyllithium [prepared from 0.53 moles ofn-butyllithium and 39.5 g of furan by the procedure of J. Org. Chem. 27,1216 (1962)] in 350 ml. of ether and ca. 200 ml of hexane at -78° C. isadded a solution of 57.9 g of 4-chlorobutanol [Chem. Abstr., 59, 7579F(1963)] in 80 ml of ether during 25 minutes. The mixture is warmed to 0°C. during 20 minutes, stirred at 0° C. for 15 minutes, and treated with140 ml of saturated ammonium chloride. The ether phase is washed withwater and brine, dried over magnesium sulfate and potassium carbonatemixture, and concentrated to give a liquid, pmr spectrum (CDCl₃): 3.59(triplet, CH₂ Cl) and 4.70 (triplet, CH₂ CHOH).

EXAMPLE 60 Preparation of 4-carbethoxymethylthio)-1-(2-furyl)-1-butanol

To a stirred, refluxing mixture of 76 g of ethyl mercaptoacetate, 79.5 gof 4-chloro-1-(2-furyl)-1-butanol, and 10 ml of 1.5M sodium ethoxide inethanol is added an additional 300 ml of 1.5M sodium ethoxide during 15minutes. The resulting mixture is stirred at reflux for 3 hours, cooled,and concentrated to remove most of the ethanol. The residue ispartitioned with ether and water. The ether phase is washed with brineand dried over potassium carbonate. The solution is concentrated,diluted with xylene, and again concentrated to give an oil, pmr spectrum(CDCl₃): 3.24 (singlet, --S--CH₂ --CO₂ C₂ H₅) and 4.70 (triplet, CH₂CHOH).

EXAMPLE 61 Preparation of2-(5-carboxy-4-thiapentyl)-4-hydroxycyclopent-2-en-1-one

A stirred solution of 125 g of4-(carbethoxymethylthio)-1-(2-furyl)-1-butanol, 22.4 g of sodiumformate, 250 ml of formic acid, and 400 mg of hydroquinone in 2000 ml ofdioxane and 1330 ml of water is refluxed for 20 hours.

The solution, containing crude3-hydroxy-2[3-(carbethoxymethylthio)propyl]cyclopent-4-en-1-one, iscooled and treated during 10 minutes with 75 ml of sulfuric acid(d═1.84) with stirring. The stirred solution is refluxed for 16 hours,cooled, saturated with sodium chloride, and extracted with ethylacetate. The extract is washed with brine, dried over magnesium sulfate,and concentrated. The residue is subjected to chromatography on silicagel with chloroform progressively enriched in ether, ether, and etherprogressively enriched in acetone to afford the subject compound as anoil.

EXAMPLE 62 Preparation of2-(5-carbotrimethylsilyloxy-4-thiapentyl)-4-trimethylsiloxycyclopent-2-en-1-one

To a stirred solution of 28.4 g of4-hydroxy-2-[4-(carboxymethylthio)butyl 9 cyclopent-2-en-1-one and 76ml. of hexamethyldisilazane in 330 ml of pyridine at 5° C. is added 38ml of chlorotrimethylsilane during 5 minutes. The mixture is stirred atambient temperature for 3.5 hours, at 45° C. for 5 minutes, and thenevaporated to remove solvent. The residue is slurried with 1000 ml ofpetroleum ether and filtered. The filtrate is treated with charcoal andfiltered; this filtrate is concentrated with the aid of toluene to givea liquid, pmr spectrum (CDCl₃): 0.18 (singlet, trimethylsiloxy group)and 0.28 (singlet, trimethylsiloxycarbonyl group).

EXAMPLE 65 Preparation of nat(and ent)-11,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor prostanoicacid

A solution of nat(andent(-11,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostanoicacid (800 mg) in 50 ml of ethyl acetate is hydrogenated in a Parrapparatus using 500 mg of 5% rhodium-on-carbon. The catalyst is removedby filtration and the filtrate is taken to dryness to furnish the titledproduct.

EXAMPLES 66-68

Hydrogenation of the prostenoic acids listed in Table II below in ethylacetate using a rhodium-on-carbon catalyst in accordance with the methoddescribed in Example 65 gives the prostanoic acids of the table.

                  Table III                                                       ______________________________________                                                13-trans-                                                                     prostenoic acid                                                       Example of Example   Prostanoic Acid                                          ______________________________________                                        66      74           nat-15S,16R-(and                                                              ent-15R,16S)-11α,15-dihydroxy-                                          9-oxo-15,16-trimethylene                                                      prostanoic acid                                          67      75           nat-15S,16R-(and                                                              ent-15R,16R)-11α,15-dihydroxy-                                          9-oxo-15,16-trimethylene                                                      protanoic acid                                           68      76           nat-(and ent)-11α,                                                      16-dihydroxy-9-oxo-16,17-tetra-                                               methylene-18,19,20-trinor                                                     prostanoic acid                                          ______________________________________                                    

EXAMPLE 69 Preparation of nat(andent)-11α,15-Dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis,13-trans-prostadienoicAcid

A 6.48 ml solution of 2.3M n-butyllithium in hexane is added, at 0° C.under nitrogen, to a solution of 1.64 g of thiophenol in 45 ml of ether.After one hour at 0° C. a solution of 5.85 g oftri-n-butylphosphine-copper complex in 140 ml of ether is added and themixture is stored in a freezer overnight. To a solution of 4.54 g of1-(trans-2-iodovinyl)-1-trimethylsilyloxycyclohexane in 8 ml of tolueneat -40° C. under nitrogen is added, with stirring, 35 ml of a solutionof t-butyllithium. After 90 minutes a few ml of ether is added and themixture is stirred at room temperature for 15 minutes. This solution isrecooled to -78° C. and the copper solution is cooled to 31 78° C. andtransferred to the vinyl lithium solution in a steady stream. Thesolution is stirred at -78° C. for 35 minutes and a solution of 5.0 g of2-(6-carbotrimethylsilyloxyhex-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one(Ex. 51) in 10 ml of ether is added. The mixture is placed in a bath at-45° C., stirred for 3 hours and allowed to warm to -20° C. over 15minutes. A solution of 2.0 g of acetic acid in 5 ml of ether is addedafter recooling to -40° C. Saturated NH₄ Cl solution is added followedby a small amount of dilute HCl. The mixture is poured into ether. Theaqueous layer is extracted with ether. The combined ether solutions arewashed with dilute HCl, twice with water and then with saturated NaCl.The ether is dried over MgSO₄ and the solvent is removed giving a yellowoil. This is stirred in 50 ml of acetic acid:tetrahydrofuran:water(4:2:1) for 45 minutes and poured into water. The solution is extractedwith ether and the ether solution is washed with water twice and oncewith brine. The solution is dried over magnesium sulfate and the solventis removed. The residue is chromatographed on a dry column of silica geleluting with ethyl acetate containing 1% acetic acid to give 2.15 g ofnat(andent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis,13-trans-prostadienoicacid.

EXAMPLE 70 Preparation of nat(andent)-11α,15-Dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostenoicAcid

To a solution of 1.0l g of thiophenol in 30 ml of ether under nitrogenat 0° C., is added with stirring, 4.0 ml of 2.3M n-butyllithium. Themixture is stirred for one hour and then a solution of 3.61 g of coppertri-n-butyl phosphine complex in 85 ml of ether is added.

To 2.98 g of 1-(2-trans-iodovinyl)-1-trimethylsilyl-oxycyclohexane in 8ml of toluene at -45° C., under nitrogen, is added with stirring 23 mlof 0.8M t-butyllithium. Stirring and cooling are continued for 75minutes. The cooling bath is removed and the solution is stirred for 10minutes. Aa 5 ml portion of ether is added and the solution is cooled to-78° C. The copper solution is cooled to -78° C. and then added to thevinyl lithium solution via a double needle. After 30 minutes, a solutionof 3.4 g of1-(6-carbotrimethyl-silyloxyhexyl)-4-trimethylsilyloxycyclopent-2-en-1-onein ether is added. The solution is then placed in a dry ice-acetonitrilebath at -45° C. to -50° C. and stirred for 3 hours. The solution isallowed to warm to -20° C. over 20 minutes and stirred at -20° C. for 10minutes. To this solution is added 5 ml of acetic acid in 5 ml of etherfollowed by 0.5M hydrochloric acid. The solution is poured into waterand extracted with ether. The ether solution is washed with water anddried with magnesium sulfate. The solvent is removed followed by removalof most of the thiophenol. The residue is dissolved in 100 ml of amixture of acetic acid, tetrahydrofuran and water and stirred for onehour. The mixture is poured into water and extracted with ether. Theether extract is washed several times with water and dried withmagnesium sulfate. The ether is removed leaving a yellow oil. This oilis chromatographed on a dry silica gel column eluting with ether:ethylacetate 1:1. The product is isolated as a light green-yellow oil whichsolidifies on drying to give an off-white solid.

EXAMPLE 71 Preparation of nat(andent)-11α,16-Dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis,13-trans-prostadienoicAcid

A solution of 10.3 g of1-(3-tri-n-butylstannyl-2-trans-propenyl)-1-trimethylsilyloxycyclohexane(Ex. 30) in 7 ml of tetrahydrofuran is cooled in a dry ice-acetone bathunder nitrogen and treated with 8.6 ml of 2.5M n-butyllithium in hexaneduring 10 minutes. The resulting solution is stirred at -40° C. for onehour, then at -20° C. to -30° C. for another hour, recooled to -78° C.,and treated during 10 minutes with the solution of 2.68 g of copperpentyne, 7.87 ml of hexamethylphosphorus triamide and 19 ml oftetrahydrofuran. The resulting solution is stirred at -70° C. to -50° C.for one hour, recooled to -78° C., and treated with a solution of 5.8 gof2-(6-carbotrimethylsilyloxyhex-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one(Ex. 51) in 12 ml of tetrahydrofuran during 10 minutes. The mixture isthen stirred at -40° C. to -50° C. for 40 minutes, then at -20° C. to-25° C. for 25 minutes, recooled to -40° C., and poured into 500 ml ofcold, saturated ammonium chloride solution and 300 ml of ether. To theresulting mixture is added 8 ml of glacial acetic acid and it isextracted with ether. The combined ether extract is washed with water,diluted hydrochloric acid, filtered through Celite and washed again withwater and saturated sodium chloride solution. Evaporation of thesolvents at reduced pressure gives 15.2 g of oil. A solution of thiscrude oil in 175 ml of glacial acetic acid:tetrahydrofuran:water (4:2:1)is stirred at room temperature under nitrogen for 50 minutes. To themixture is added 150 ml of toluene and concentrated at reduced pressure.The crude product obtained is purified by chromatography on silica gelto give nat(andent)-11α,16-dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis,-13-trans-prostadienoicacid.

EXAMPLE 72 Preparation of nat-15S,16R(and ent-15R,16S) andnat-15R,16S-(andent-15S,16R)-11α,15-Dihydroxy-9-oxo-15,16-trimethylene-13-trans-5-cis-prostadienoicAcid

To a solution of 1.44 g of thiophenol in 40 ml of ether under nitrogenat 0° C. is added with stirring, 5.65 ml of 2.3M n-butyllithium. Afterone hour of stirring at 0° C. a solution of bis-tri-n-butylphosphinecopper iodide complex in 100 ml of ether is added and the solution isstored overnight in a freezer.

To 4.76 g of 1R,2S(and1S,2R)-1-(trans-2-iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentone in10 ml of toluene under nitrogen at -45° C., is added with stirring, 32.5ml of 0.08M t-butyllithium. After stirring for 90 minutes at -45° C. thesolution is removed from the cooling bath and stirred 15 minutes. Thesolution is cooled to -78° C. The copper solution is cooled to -78° C.and then added to the vinyl lithium solution. After 30 minutes asolution of 4.4 g of1-(6-carbotrimethylsilyloxyhex-2-cis-enyl)-4-trimethylsilyoxycyclopent-2-en-1-onein 20 ml of ether is added. The solution is stirred at -45° C. for 3hours and then allowed to warm to -20° C. over a 30 minute period. Thesolution is stirred at -20° C. for 15 minutes and then a solution of 2.5ml of acetic acid in 15 ml of ether is added followed by dilutehydrochloric acid. The mixture is extracted with ether. The etherextract is washed with saturated sodium chloride solution and dried withmagnesium sulfate. The solvent is removed giving a yellow oil. This oilis stirred in 70 ml of acetic acid:tetrahydrofuran:water (4:2:1) for onehour, poured into water and extracted with ether. The extract is driedwith magnesium sulfate and the ether is removed. The residue ischromatographed on a dry colummn of silica gel, eluting with ether togive the separated isomers.

EXAMPLE 74-155

In the manner described hereinabove for Examples 69-72, the9-oxo-prostaglandins shown in Table IV are prepared from the indicatedvinyl iodide or vinyl tin compounds and the indicatedcyclopent-2-en-1-one. In the reactions involving the4-hydroxycyclopent-2-en-1-one, these were first converted to theircorresponding bis-trimethylsilyloxy derivatives as described hereinabovefor Examples 51 and 52. In those cases where two diastereoisomers areformed in the conjugate-addition, only one of the diastereoisomers islisted in Table IV. It should be understood that the otherdiastereoisomer is also formed which in its nat and ent forms has anopposite (mirror image) configuration at the assymmetric carbon atoms onthe β-chain (the chain containing C₁₃ . . . C₁₄ etc.) to that of therespective nat and ent forms of the listed diastereoisomer; both ofthese diastereoisomers are claimed in this invention as well as theircomponent enantiomers.

                                      Table IV                                    __________________________________________________________________________                                 Product 9-oxo-prostaglandin and its                   Vinyl Iodide or Vinyl   diastereoisomer and ethyl ester                  Example                                                                            Tin of Example                                                                           Cyclopent-2-en-1-one                                                                       where applicable (see hereinabove)               __________________________________________________________________________    74    29a       2-(6-carboxyhexyl)-4-hy-                                                                   nat-15S,16R-(and ent-15R,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethyl-                                           lene-13-trans-prostenoic acid                    75   36         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15S,16S-(and ent-15R,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-13-trans-prostenoic acid                    76   31         2-(6-carboxyhexyl)-4-hy-                                                                   nat-(and ent)-11α,15-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                  oxo-15,16-tetramethylene-17,18,19,-                                           20-tetranor-13-trans-prostenoic acid             77   32         2-(6-carboxyhexyl)-4-hy-                                                                   nat-(and ent)-11α,15-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                  oxo-15,16-trimethylene-17,18,19,20-                                           tetranor-13-trans-prostenoic acid                78   33         2-(6-carboxyhexyl)-4-hy-                                                                   nat-(and ent)-11α,15-dihyroxy-15-                          droxycyclopent-2-en-1-one                                                                  16-pentamethylene-17,18,19,20-tetra-                                          nor-13-trans-prostenoic acid                     79   34         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15S,17R-(and ent-15R,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,17-dimethy-                                             lene-13-trans-prostenoic acid                    80   35         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15S,17S-(and ent-15R,17R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,17-dimethy-                                             lene-13-trans-prostenoic acid                    81   37         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15S,16R-(and ent-15R,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-tetra-                                               methylene-13-trans-prostenoic acid               82   38         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15S,16S-(and ent-15R,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-tetra-                                               methylene-13-trans-prostenoic acid               83   39         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15R,16S-(and ent-15S,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-16-(3-trifluoromethylphenoxy)-                                           17,18,19,20-tetranor-13-trans-                                                prostenoic acid                                  84   40         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15R,16R-(and ent-15S,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-16-(3-trifluoromethylphenoxy)-                                           17,18,19,20-tetranor-13-trans-                                                prostenoic acid                                  85   30         2-(6-carboxyhexyl)-4-hy-                                                                   nat-(and ent)-11α,16-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                  oxo-16,17-tetramethylene-18,19,20-                                            trinor-13-trans-prostenoic acid                  86   41         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15R,16S-(and ent-15S,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-16-(4-fluorophenoxy(-17,18,19,-                                          20-tetranor-13-trans-prostenoic acid             87   42         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15R,16R-(and ent-15S,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-16-(4-fluorophenoxy)-17,18,19,-                                          20-tetranor-13-trans-prostenoic acid             88   43         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15R,16S-(and ent-15S,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-16-(3-chlorophenoxy)-17,18,19,-                                          20-tetranor-13-trans-prostenoic acid             89   44         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15R,16R-(and ent-15S,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-16-(3-chlorophenoxy)-17,18,19,-                                          20-tetranor-13-trans-prostenoic acid             90   45         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15S,17R-(and ent-15R,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,17-trimethy-                                            lene-19,20-dinor-13-trans-prostenoic                                          acid                                             91   46         2-(6-carboxyhexyl)-4-hy-                                                                   nat-15S,17S-(and ent-15R,17R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,17-trimethy-                                            lene-19,20-dinor-13-trans-prostenoic                                          acid                                             92   47         2-(6-carboxyhexyl)-4-hy-                                                                   nat-16R,17S-(and ent-16S,17R)-11α,-                        droxycyclopent-2-en-1-one                                                                  16-dihydroxy-9-oxo-16,17-trimethy-                                            lene-20-methyl-13-trans-prostenoic                                            acid                                             93   48         2-(6-carboxyhexyl)-4-hy-                                                                   nat-16R,17R-(and ent-16S,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                  16-dihydroxy-9-oxo-16,17-trimethy-                                            lene-20-methyl-13-trans-prostenoic                                            acid                                             94   49         2-(6-carboxyhexyl)-4-hy-                                                                   nat-16R,17S-(and ent-16S,17R)-11α,-                        droxycyclopent-2-en-1-one                                                                  16-dihydroxy-9-oxo-16,17-trimethy-                                            lene-16-(3-trifluoromethylphenoxy)-                                           18,19,20-trinor-13-trans-prostenoic                                           acid                                             95   50         2-(6-carboxyhexyl)-4-hy-                                                                   nat-16R,17R-(and ent-16S,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                  16-dihydroxy-9-oxo-16,17-trimethy-                                            lene-16-(3-trifluoromethylphenoxy)-                                           18,19,20-trinor-13-trans-prostenoic                                           acid                                             96    29a       2-(5-carboxypentyl)-4-hy-                                                                  nat-15S,16R-(and ent-15R,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-2-nor-13-trans-prostenoic acid              97   36         2-(5-carboxypentyl)-4-hy-                                                                  nat-15S,16S-(and ent-15R,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-2-nor-13-trans-prostenoic acid              98   31         2-(5-carboxypentyl)-4-hy-                                                                  nat-(and ent)-11α,15-dihyroxy-9-                           droxycyclopent-2-en-1-one                                                                  oxo-15,16-tetramethylene-,17,18,-                                             19,20-pentanor-13-trans-prostenoic                                            acid                                             99   32         2-(5-carboxypentyl)-4-hy-                                                                  nat-(and ent)-11α,15-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                  oxo-15,16-trimethylene-2,17,18,-                                              19,20-pentanor-13-trans-prostenoic                                            acid                                             100  33         2-(5-carboxypentyl)-4-hy-                                                                  nat-(and ent)-11α,15-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                  oxo-15,16-pentamethylene-2,17,18,-                                            19,20-pentanor-13-trans-prostenoic                                            acid                                             101  34         2-(5-carboxypentyl)-4-hy-                                                                  nat-15S,17R-(and ent-15R,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,17-dimethy-                                             lene-2-nor-13-trans-prostenoic acid              102  35         2-(5-carboxypentyl)-4-hy-                                                                  nat-15S,17S-(and ent-15R,17R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,17-dimethy-                                             lene-2-nor-13-trans-prostenoic acid              103  39         2-(5-carboxypentyl)-4-hy-                                                                  nat-15R,16S-(and ent-15S,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy--oxo-15,16-trimethy-                                             lene-16-(3-trifluoromethylphenoxy)-                                           7,17,18,19,20-pentanor-13-trans-                                              prostenoic acid                                  104  40         2-(5-carboxypentyl)-4-hy-                                                                  nat-15R,16R-(and ent-15S,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy--oxo-15,16-trimethy-                                             lene-16-(3-trifluoromethylphenoxy)-                                           2,17,18,19,20-pentanor-13-trans-                                              prostenoic acid                                  105   29a       2-(7-carboxyheptyl)-4-hy-                                                                  nat-15S,16R-(and ent-15R,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-1-homo-13-trans-prostenoic acid             106  36         2-(7-carboxyheptyl)-4-hy-                                                                  nat-15S,16S-(and ent-15R,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-1-homo-13-trans-prostenoic acid             107  31         2-(7-carboxyheptyl)-4-hy-                                                                  nat-(and ent)-11α,15-dihydroxy-9-                          droxycyclopent-2-en-1-one                                                                  oxo-15,16-tetramethylene-17,18,19,-                                           20-tetranor-1-homo-13-trans-prosten-                                          oic acid                                         108  37         2-(7-carboxyheptyl)-4-hy-                                                                  nat-15S,16R-(and ent-15R,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-tetramethy-                                          lene-1-homo-13-trans-prostenoic acid             109  38         2-(7-carboxyheptyl)-4-hy-                                                                  nat-15S,16S-(and ent-15R,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-tetramethy-                                          lene-1-homo-13-trans-prostenoic acid             110  41         2-(7-carboxyheptyl)-4-hy-                                                                  nat-15R,16S-(and ent-15S,16R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-16-(4-fluorophenoxy)-1-homo-                                             17,18,19,20-tetranor-13-trans-                                                prostenoic acid                                  111  42         2-(7-carboxyheptyl)-4-hy-                                                                  nat-15R,16R-(and ent-15S,16S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,16-trimethy-                                            lene-16-(4-fluorophenoxy)-1-homo-                                             17,18,19,20-tetranor-13-trans-                                                prostenoic acid                                  112  45         2-(8-carboxyoctyl)-4-hy-                                                                   nat-15S,17R-(and ent-15R,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,17-trimethy-                                            lene-19,20-dinor-1a,1b-dihomo-13-                                             trans-prostenoic acid                            113  46         2-(8-carboxyoctyl)-4-hy-                                                                   nat-15S,17S-(and ent-15R,17R)-11α,-                        droxycyclopent-2-en-1-one                                                                  15-dihydroxy-9-oxo-15,17-trimethy-                                            lene-19,20-dinor-1a,1b-dihomo-13-                                             trans-prostenoic acid                            114  47         2-(8-carboxyoctyl)-4-hy-                                                                   nat-16R,17S-(and ent-16S,17R)-11α,-                        droxycyclopent-2-en-1-one                                                                  16-dihydroxy-9-oxo-16,17-trimethy-                                            lene-20-methyl-1a,1b-dihomo-13-                                               trans-prostenoic acid                            115  48         2-(8-carboxyoctyl)-4-hy-                                                                   nat-16R,17R-(and ent-16S,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                  16-dihydroxy-9-oxo-16,17-trimethy-                                            lene-20-methyl-1a,1b-dihomo-13-                                               trans-prostenoic acid                            116  49         2-(8-carboxyoctyl)-4-hy-                                                                   nat-16R,17S-(and ent-16S,17R)-11α,-                        droxycyclopent-2-en-1-one                                                                  16-dihydroxy-9-oxo-16,17-trimethy-                                            lene-16-(3-trifluoromethylphenoxy)-                                           18,19,20-trinor-1a,1b-dihomo-13-                                              trans-prostenoic acid                            117  50         2-(8-carboxyoctyl)-4-hy-                                                                   nat-16R,17R-(and ent-16S,17S)-11α,-                        droxycyclopent-2-en-1-one                                                                  16-dihydroxy-9-oxo-16,17-trimethy-                                            lene-16-(3-trifluoromethylphenoxy)-                                           18,19,20-trinor-1a,1b-dihomo-13-                                              trans-prostenoic acid                            118   29a       2-(6-carboxyhex-2-cis-                                                                     nat-15S,16R-(and ent-15R,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-13-trans-5-cis-prostadienoic                                             acid                                             119  36         2-(6-carboxyhex-2-cis-                                                                     nat-15S,16S-(and ent-15R,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-13-trans-5-cis-prostadienoic                                             acid                                             120  32         2-(6-carboxyhex-2-cis-                                                                     nat-(and ent)-11α,15-dihydroxy-9-                          enyl)-4-hydroxycyclo-                                                                      oxo-15,16-trimethylene-17,18,19,-                                pent-2-en-1-one                                                                            20-tetranor-13-trans-5-cis-prosta-                                            dienoic acid                                     121  33         2-(6-carboxyhex-2-cis-                                                                     nat-(and ent)-11α,15-dihydroxy-9-                          enyl)-4-hydroxycyclo-                                                                      oxo-15,16-pentamethylene-17,18,-                                 pent-2-en-1-one                                                                            19,20-tetranor-13-trans-5-cis-                                                prostadienoic acid                               122  34         2-(6-carboxyhex-2-cis-                                                                     nat-15S,17R-(and ent-15R,17S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,17-dimethy-                                pent-2-en-1-one                                                                            lene-13-trans-5-cis-prostadienoic                                             acid                                             123  35         2-(6-carboxyhex-2-cis-                                                                     nat-15S,17S-(and ent-15R,17R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,17-dimethy-                                pent-2-en-1-one                                                                            lene-13-trans-5-cis-prostadienoic                                             acid                                             124  37         2-(6-carboxyhex-2-cis-                                                                     nat-15S,16R-(and ent-15R,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-tetramethy-                             pent-2-en-1-one                                                                            lene-13-trans-5-cis-prostadienoic                                             acid                                             125  38         2-(6-carboxyhex-2-cis-                                                                     nat-15S,16S-(and ent-15R,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-tetramethy-                             pent-2-en-1-one                                                                            lene-13-trans-5-cis-prostadienoic                                             acid                                             126  39         2-(6-carboxyhex-2-cis-                                                                     nat-15R,16S-(and ent-15S,15R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-16-(3-trifluoromethylphenoxy)-                                           17,18,19,20-tetranor-13-trans-5-                                              cis-prostadienoic acid                           127  40         2-(6-carboxyhex-2-cis-                                                                     nat-15R,16R-(and ent-15S,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-16-(3-trifluoromethylphenoxy)-                                           17,18,19,20-tetranor-13-trans-5-                                              cis-prostadienoic acid                           128  41         2-(6-carboxyhex-2-cis-                                                                     nat-15R,16S-(and ent-15S,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-16-(4-fluorophenoxy)-17,18,19,-                                          20-tetranor-13-trans-5-cis-prosta-                                            dienoic acid                                     129  42         2-(6-carboxyhex-2-cis-                                                                     nat-15R,16R-(and ent-15S,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-16-(4-fluorophenoxy)-17,18,19,-                                          20-tetranor-13-trans-5-cis-prosta-                                            dienoic acid                                     130  43         2-(6-carboxyhex-2-cis-                                                                     nat-15R,16S-(and ent-15S,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-16-(3-chlorophenoxy)-17,18,-                                             19,20-tetranor-13-trans-5-cis-pros-                                           tadienoic acid                                   131  44         2-(6-carboxyhex-2-cis-                                                                     nat-15R,16R-(and ent-15S,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-16-(3-chlorophenoxy)-17,18,-                                             19,20-tetranor-13-trans-5-cis-pros-                                           tadienoic acid                                   132  45         2-(6-carboxyhex-2-cis-                                                                     nat-15S,17R-(and ent-15R,17S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,17-trimethy-                               pent-2-en-1-one                                                                            lene-19,20-dinor-13-trans-5-cis-                                              prostadienoic acid                               133  46         2-(6-carboxyhex-2-cis-                                                                     nat-15S,17S-(and ent-15R,17R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,17-trimethy-                               pent-2-en-1-one                                                                            lene-19,20-dinor-13-trans-5-cis-                                              prostadienoic acid                               134  47         2-(6-carboxyhex-2-cis-                                                                     nat-16R,17S-(and ent-16S,17R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      16-dihydroxy-9-oxo-16,17-trimethy-                               pent-2-en-1-one                                                                            lene-20-methyl-13-trans-5-cis-pros-                                           tadienoic acid                                   135  48         2-(6-carboxyhex-2-cis-                                                                     nat-16R,17R-(and ent-16S,17S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      16-dihydroxy-9-oxo-16,17-trimethy-                               pent-2-en-1-one                                                                            lene-20-methyl-13-trans-5-cis-pros-                                           tadienoic acid                                   136  49         2-(6-carboxyhex-2-cis-                                                                     nat-16R,17S-(and ent-16S,17R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      16-dihydroxy-9-oxo-16,17-trimethy-                               pent-2-en-1-one                                                                            lene-17-(3-trifluoromethylphenoxy)-                                           18,19,20-trinor-13-trans-5-cis-                                               prostadienoic acid                               137  50         2-(6-carboxyhex-2-cis-                                                                     nat-16R,17R-(and ent-16S,17S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      16-dihydroxy-9-oxo-16,17-trimethy-                               pent-2-en-1-one                                                                            lene-17-(3-trifluoromethylphenoxy)-                                           18,19,20-trinor-13-trans-5-cis-                                               prostadienoic acid                               138   29a       2-(8-carboxyoct-2-cis-                                                                     nat-15S,16R-(and ent-15R,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-1a,1b-dihomo-13-trans-5-cis-                                             prostadienoic acid                               139  36         2-(8-carboxyoct-2-cis-                                                                     nat-15S,16S-(and ent-15R,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-1a,1b-dihomo-13-trans-5-cis-                                             prostadienoic acid                               140  31         2-(8-carboxyoct-2-cis-                                                                     nat-(and ent)-11α,15-dihydroxy-9-                          enyl)-4-hydroxycyclo-                                                                      oxo-15,16-tetramethylene-1a,1b-di-                               pent-2-en-1-one                                                                            homo-17,18,19,20-tetranor-13-trans-                                           5-cis-prostadienoic acid                         141  37         2-(8-carboxyoct-2-cis-                                                                     nat-15S,16R-(and ent-15R,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-tetramethy-                             pent-2-en-1-one                                                                            lene-1a,1b-dihomo-13-trans-5-cis-                                             prostadienoic acid                               142  38         2-(8-carboxyoct-2-cis-                                                                     nat-15S,16S-(and ent-15R,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-hydroxy-9-oxo-15,16-tetramethy-                               pent-2-en-1-one                                                                            lene-1a,1b-dihomo-13-trans-5-cis-                                             prostadienoic acid                               143  39         2-(8-carboxyoct-2-cis-                                                                     nat-15R,16S-(and ent-15S,16R)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-16-(3-trifluoromethylphenoxy)-                                           1a,1b-dihomo-17,18,19,20-tetranor-                                            13-trans-5-cis-prostadienoic acid                144  40         2-(8-carboxyoct-2-cis-                                                                     nat-15R,16R-(and ent-15S,16S)-11α,-                        enyl)-4-hydroxycyclo-                                                                      15-dihydroxy-9-oxo-15,16-trimethy-                               pent-2-en-1-one                                                                            lene-16-(3-trifluoromethylphenoxy)-                                           1a,1b-dihomo-17,18,19,20-tetranor-                                            13-trans-5-cis-prostadienoic acid                145   29a       2-(6-carboxy-5-oxa-hex-                                                                    nat-15S,16R-(and ent-15R,16S)-11α,-                        yl)-4-hydroxycyclopent-                                                                    15-dihydroxy-3-oxa-9-oxo-15,16-tri-                              2-en-1-one   methylene-13-trans-prostenoic acid               146  36         2-(6-carboxy-5-oxa-hex-                                                                    nat-15S,16S-(and ent-15R,16R)-11α,-                        yl)-4-hydroxycyclopent-                                                                    15-dihydroxy-3-oxa-9-oxo-15,16-tri-                              2-en-1-one   methylene-13-trans-prostenoic acid               147  31         2-(6-carboxy-5-oxa-hex-                                                                    nat-(and ent)-11α,15-dihydroxy-3-                          yl)-4-hydroxycyclopent-                                                                    oxa-9-oxo-15,16-tetramethylene-                                  2-en-1-one   17,18,19,20-tetranor-13-trans-                                                prostenoic acid                                  148  43         2-(6-carboxy-4-methyl-                                                                     nat-15R,16S-(and ent-15S,16R)-11α,-                        hex-2-cis-enyl)-4-hydroxy-                                                                 15-dihydroxy-4-methyl-9-oxo-15,16-                               cyclopent-2-en-1-one                                                                       trimethylene-16-(3-chlorophenoxy)-                                            17,18,19,20-tetranor-13-trans-                                                prostenoic acid                                  149  44         2-(6-carboxy-4-methyl-                                                                     nat-15R,16R-(and ent-15S,16S)-11α,-                        hex-2-cis-enyl)-4-hydroxy-                                                                 15-dihydroxy-4-methyl-9-oxo-15,16-                               cyclopent-2-en-1-one                                                                       trimethylene-16-(3-chlorophenoxy)-                                            17,18,19,20-tetranor-13-trans-                                                prostenoic acid                                  150  45         2-(6-carboxy-4-methyl-                                                                     nat-15S,17R-(and ent-15R,17S)-11α,-                        hex-2-cis-enyl)-4-hydroxy-                                                                 15-dihydroxy-4-methyl-9-oxo-15,17-                               cyclopent-2-en-1-one                                                                       trimethylene-19,20-dinor-13-trans-                                            prostenoic acid                                  151  46         2-(6-carboxy-4-methyl-                                                                     nat-15S,17S-(and ent-15R,17R)-11α,-                        hex-2-cis-enyl)-4-hydroxy-                                                                 15-dihydroxy-4-methyl-9-oxo-15,17-                               cyclopent-2-en-1-one                                                                       trimethylene-19,20-dinor-13-trans-                                            prostenoic acid                                  152  47         2-(6-carboxy-4-methyl-                                                                     nat-16R,17S-(and ent-16S,17R)-11α,-                        hex-2-cis-enyl)-4-hydroxy-                                                                 16-dihydroxy-4-methyl-9-oxo-16,17-                               cyclopent-2-en-1-one                                                                       trimethylene-20-methyl-13-trans-                                              prostenoic acid                                  153  48         2-(6-carboxy-4-ethylhex-                                                                   nat-16R,17R-(and ent-16S,17S)-11α,-                        2-cis-enyl)-4-hydroxy-                                                                     16-dihydroxy-4-ethyl-9-oxo-16,17-                                cyclopent-2-en-1-one                                                                       trimethylene-20-methyl-13-trans-                                              prostenoic acid                                  154  49         2-(6-carboxy-4 ethylhex-                                                                   nat-16R,17S-(and ent-16S,17R)-11α,-                        2-cis-enyl)-4-hydroxy-                                                                     16-dihydroxy-4-ethyl-9-oxo-15,17-                                cyclopent-2-en-1-one                                                                       trimethylene-17-(3-trifluoromethyl-                                           phenoxy)-18,19,20-trinor-13-trans-                                            prostenoic acid                                  155  50         2-(6-carboxy-4-ethylhex-                                                                   nat-16R,17R-(and ent-16S,17S)-11α,-                        2-cis-enyl)-4-hydroxy-                                                                     16-dihydroxy-4-ethyl-9-oxo-15,17-                                cyclopent-2-en-1-one                                                                       trimethylene-17-(3-trifluoromethyl-                                           phenoxy)-18,19,20-trinor-13-trans-                                            prostenoic acid                                  __________________________________________________________________________

EXAMPLES 156-173

In the manner of Examples 69-72, the 9-oxo-11α-hydroxy prostaglandinmethyl esters listed in Table V are prepared from the indicatedcyclopent-2-en-1-one and vinyl iodide or vinyl tin compound indicated.

In those cases where two diastereoisomers are formed in theconjugate-addition both are obtained in an optically active form andonly one of the diastereoisomers is listed in Table V. It should beunderstood that the other diastereoisomer is also formed which in itsnat or ent forms has an opposite (mirror image) configuration at theassymmetric carbon atoms on the β-chain (the chain containing C₁₃ -C₁₄ .. . etc.) to that of the respective nat or ent forms of the listeddiastereoisomer; both of these diastereoisomers are claimed in thisinvention.

                                      Table V                                     __________________________________________________________________________                                     Product optically active 9-oxo-                   Vinyl Iodide or Vinyl       prostaglandin and its optically              Example                                                                            Tin of Example                                                                           Cyclopent-2-en-1-one                                                                           active diastereoisomer                       __________________________________________________________________________    156   29a       2-(6-carbomethoxyhexyl)-                                                                       nat-methyl-15S,16R-11α,15-dihydroxy                                     -                                                            4(R)-trimethylsilyloxy-                                                                        9-oxo-15,16-trimethylene-13-trans-                           cyclopent-2-en-1-one                                                                           prostenoate                                  157  36         2-(6-carbomethoxyhexyl)-                                                                       nat-methyl-15S,16S-11α,15-dihydroxy                                     -                                                            4(R)-trimethylsilyloxy-                                                                        9-oxo-15,16-trimethylene-13-trans-                           cyclopent-2-en-1-one                                                                           prostenoate                                  158  31         2-(6-carbomethoxyhexyl)-                                                                       nat-methyl-11α,15-dihydroxy-9-oxo-                                      .                                                            4(R)-trimethylsilyloxy-                                                                        15,16-tetramethylene-17,18,19,20-                            cyclopent-2-en-1-one                                                                           tetranor-13-trans-prostenoate                159  30         2-(6-carbomethoxyhexyl)-                                                                       nat-methyl-11α,16-dihydroxy-9-oxo-                                      7                                                            4(R)-trimethylsilyloxy-                                                                        16,17-tetramethylene-18,19,20-tri-                           cyclopent-2-en-1-one                                                                           nor-13-trans-prostenoate                     160  39         2-(6-carbomethoxyhexyl)-                                                                       nat-methyl-15R,16S-11α,15-dihydroxy                                     -                                                            4(R)-trimethylsilyloxy-                                                                        9-oxo-15,16-trimethylene-16-(3-tri-                          cyclopent-2-en-1-one                                                                           fluoromethylphenoxy)-17,18,19,20-                                             tetranor-13-trans-prostenoate                __________________________________________________________________________                                     Product optically active 9-oxo-                   Vinyl Iodide or Vinyl       prostaglandin and its optically              Example                                                                            Tin of Example                                                                           Cyclopent-2-en-1-one                                                                           active diastereoisomer                       __________________________________________________________________________    161  40         2-(6-carbomethoxyhexyl)-                                                                       nat-methyl-15R,16R-11α,15-dihydroxy                                     -                                                            4(R)-trimethylsilyloxy-                                                                        9-oxo-15,16-trimethylene-16-(3-tri-                          cyclopent-2-en-1-one                                                                           fluoromethylphenoxy)-17,18,19,20-                                             tetranor-13-trans-prostenoate                162   29a       2-(6-carbomethoxyhexyl)-                                                                       ent-methyl-15R,16S-11α,15-dihydroxy                                     -                                                            4(S)-trimethylsilyloxy-                                                                        9-oxo-15,16-trimethylene-13-trans-                           cyclopent-2-en-1-one                                                                           prostenoate                                  163  36         2-(6-carbomethoxyhexyl)-                                                                       ent-methyl-15R,16R-11α,15-dihydroxy                                     -                                                            4(S)-trimethylsilyloxy-                                                                        9-oxo-15,16-trimethylene-13-trans-                           cyclopent-2-en-1-one                                                                           prostenoate                                  164  31         2-(6-carbomethoxyhexyl)-                                                                       ent-methyl-11α,15-dihydroxy-9-oxo-                                      O                                                            4(S)-trimethylsilyloxy-                                                                        15,16-tetramethylene-17,18,19,20-                            cyclopent-2-en-1-one                                                                           tetranor-13-trans-prostenoate                165  30         2-(6-carbomethoxyhexyl)-                                                                       ent-methyl-11α,16-dihydroxy-9-oxo-                                      N                                                            4(S)-trimethylsilyloxy-                                                                        16,17-tetramethylene-18,19,20-tri-                           cyclopent-2-en-1-one                                                                           nor-13-trans-prostenoate                     __________________________________________________________________________                                     Product optically active 9-oxo-                   Vinyl Iodide or Vinyl       prostaglandin and its optically              Example                                                                            Tin of Example                                                                           Cyclopent-2-en-1-one                                                                           active diastereoisomer                       __________________________________________________________________________    166  39         2-(6-carbomethoxyhexyl)-                                                                       ent-methyl-15S,16R-11α,15-dihydroxy                                     -                                                            4(S)-trimethylsilyloxy-                                                                        9-oxo-15,16-trimethylene-16-(3-tri-                          cyclopent-2-en-1-one                                                                           fluoromethylphenoxy)-17,18,19,20-                                             tetranor-13-trans-prostenoate                167  40         2-(6-carbomethoxyhexyl)-                                                                       ent-methyl-15S,16S-11α,15-dihydroxy                                     -                                                            4(S)-trimethylsilyloxy-                                                                        9-oxo-15,16-trimethylene-16-(3-tri-                          cyclopent-2-en-1-one                                                                           fluoromethylphenoxy)-17,18,19,20-                                             tetranor-13-trans-prostenoate                168   29a       2-(6-carbomethoxyhex-2-                                                                        nat-methyl-15S,16R-11α,15-dihydroxy                                     -                                                            cis-enyl)-4(R)-trimethyl-                                                                      9-oxo-15,16-trimethylene-13-trans-                           silyloxycyclopent-2-en-1-                                                                      5-cis-prostenoate                                            one                                                           169  36         2-(6-carbomethoxyhex-2-                                                                        nat-methyl-15S,16S-11α,15-dihydroxy                                     -                                                            cis-enyl)-4(R)-trimethyl-                                                                      9-oxo-15,16-trimethylene-13-trans-                           silyloxycyclopent-2-en-1-                                                                      5-cis-prostadienoate                                         one                                                           170  31         2-(6-carbomethoxyhex-2-                                                                        nat-methyl-11α,15-dihydroxy-9-oxo-                                      B                                                            cis-enyl-4(R)-trimethyl-                                                                       15,16-tetramethylene-17,18,19,20-                            silyloxycyclopent-2-en-1-                                                                      tetranor-13-trans-5-cis-prosta-                              one              dienoate                                     __________________________________________________________________________                                     Product optically active 9-oxo-                   Vinyl Iodide or Vinyl       prostaglandin and its optically              Example                                                                            Tin of Example                                                                           Cyclopent-2-en-1-one                                                                           active diastereoisomer                       __________________________________________________________________________    171  30         2-(6-carbomethoxyhex-2-                                                                        nat-methyl-11α,16-dihydroxy-9-oxo-                                      S                                                            cis-enyl)-4-(R)-trimethyl-                                                                     16,17-tetramethylene-18,19,20-tri-                           silyloxycyclopent-2-en-1-                                                                      nor-13-trans-5-cis-prostadienoate                            one                                                           172  39         2-(6-carbomethoxyhex-2-                                                                        nat-methyl-15R,16S-11α,15-dihydroxy                                     -                                                            cis-enyl)-4(R)-trimethyl-                                                                      9-oxo-15,16-trimethylene-16-(3-tri-                          silyloxycyclopent-2-en-1-                                                                      fluoromethylphenoxy)-17,18,19,20-                            one              tetranor-13-trans-5-cis-prosta-                                               dienoate                                     173  40         2-(6-carbomethoxyhex-2-                                                                        nat-methyl-15R,16R-11α,15-dihydroxy                                     -                                                            cis-enyl)-4(R)-trimethyl-                                                                      9-oxo-15,16-trimethylene-16-(3-tri-                          silyloxycyclopent-2-en-1-                                                                      fluoromethylphenoxy)-17,18,19,20-                            one              tetranor-13-trans-5-cis-prosta-                                               dienoate                                     __________________________________________________________________________         Vinyl Iodide or Vinyl       Product 9-oxo-prostaglandin and its          Example                                                                            Tin of Example                                                                           Cyclopent-2-en-1-one                                                                           diastereoisomer                              __________________________________________________________________________    174  31         2-(6-carbotrimethylsilyl-                                                                      nat-(and ent)-11α,15-dihydroxy-3-                      oxy-5-thiahexyl)-4-tri-                                                                        thia-9-oxo-15,16-trimethylene-                               methylsilyloxycyclo-                                                                           17,18,19,20-tetranor-13-trans-                               pent-2-en-1-one  prostenoic acid                              175   29a       2-(6-carbotrimethylsilyl-                                                                      nat-15S,16R(and ent-15R,                                                      16S)-11α,15-                                           oxy-5-thiahexyl)-4-tri-                                                                        dihydroxy-3-thia-9-oxo-15,16-tri-                            methylsilyloxycyclo-                                                                           methylene-13-trans-prostenoic acid                           pent-2-en-1-one                                               176  36         2-(6-carbotrimethylsilyl)-                                                                     nat-15S,16S-(and ent-15R,16R)-11α,-                                     0                                                            oxy-5-thiahexyl)-4-tri-                                                                        15-dihydroxy-3-thia-9-oxo-15,16-tri-                         methylsilyloxycyclo-                                                                           methylene-13-trans-prostenoic acid                           pent-2-en-1-one                                               177  30         2-(6-carbotrimethylsilyl-                                                                      nat-(and ent)-11α,16-dihydroxy-3-                      oxy-5-thiahexyl)-4-tri-                                                                        thia-9-oxo-16,17-tetramethylene-                             methylsilyloxycyclo-                                                                           18,19,20-trinor-13-trans-prostenoic                          pent-2-en-1-one  acid                                         __________________________________________________________________________         Vinyl Iodide or Vinyl       Product 9-oxo-prostaglandin and its          Example                                                                            Tin of Example                                                                           Cyclopent-2-en-1-one                                                                           diastereoisomer                              __________________________________________________________________________    178  39         2-(6-carbotrimethylsilyl-                                                                      nat-15R,16S-(and ent-15S,16R)-11α,-                                     5                                                            oxy-5-thiahexyl)-4-tri-                                                                        15-dihydroxy-3-thia-9-oxo-15,16-tri-                         methylsilyloxycyclo-                                                                           methylene-16-(3-trifluoromethyl-                             pent-2-en-1-one  phenoxy)-17,18,19,20-tetranor-13-                                             trans-prostenoic acid                        179  40         2-(6-carbotrimethylsilyl-                                                                      nat-15R,16R-(and ent-15S,16S)-11α,-                                     N                                                            oxy-5-triahexyl)-4-tri-                                                                        15-dihydroxy-3-thia-9-oxo-15,16-tri-                         methylsilyloxycyclo-                                                                           methylene-16-(3-trifluoromethyl-                             pent-2-en-1-one  phenoxy)-17,18,19,20-tetranor-13-                                             trans-prostenoic acid                        180  31         2-(5-carbotrimethylsilyl-                                                                      nat-(and ent)-11α,15-dihydroxy-3-                      oxy-4-thiapentyl)-4-tri-                                                                       thia-9-oxo-15,16-tetramethylene-                             methylsilyloxycyclopent-                                                                       4,17,18,19,20-pentanor-13-trans-                             2-en-1-one       prostenoic acid                              181   29a       2-(5-carbotrimethylsilyl-                                                                      nat-15S,16R-(and ent-15R,16S)-11α,-                                     N                                                            oxy-4-thiapentyl)-4-tri-                                                                       15-dihydroxy-3-thia-9-oxo-15,16-tri-                         methylsilyloxycyclopent-                                                                       methylene-4-nor-13-trans-prostenoic                          2-en-1-one       acid                                         __________________________________________________________________________         Vinyl Iodide or Vinyl       Product 9-oxo-prostaglandin and its          Example                                                                            Tin of Example                                                                           Cyclopent-2-en-1-one                                                                           diastereoisomer                              __________________________________________________________________________    182  36         2-(5-carbotrimethylsilyl-                                                                      nat-15S,16S-(and ent-15R,16R)-11α,-                                     O                                                            oxy-4-thiapentyl)-4-tri-                                                                       15-dihydroxy-3-thia-9-oxo-15,16-tri-                         methylsilyloxycyclopent-                                                                       methylene-4-nor-13-trans-prostenoic                          2-en-1-one       acid                                         183  30         2-(5-carbotrimethylsilyl-                                                                      nat-(and ent)-11α,16-dihydroxy-3-                      oxy-4-thiapentyl)-4-tri-                                                                       thia-9-oxo-16,17-tetramethylene-4,-                          methylsilyloxycyclopent-                                                                       18,19,20-tetranor-13-trans-prosten-                          2-en-1-one       oic acid                                     184  39         2-(5-carbotrimethylsilyl-                                                                      nat-15R,16S-(and ent-15S,16R)-11α,-                                     O                                                            oxy-4-thiapentyl)-4-tri-                                                                       15-dihydroxy-3-thia-9-oxo-15,16-                             methylsilyloxycyclopent-                                                                       trimethylene-16-(3-trifluoromethyl-                          2-en-1-one       phenoxy)-4,17,18,19,20-pentanor-13-                                           trans-prostenoic acid                        185  40         2-(5-carbotrimethylsilyl-                                                                      nat-15R,16R-(and ent-15S,16S)-11α,-                                     N                                                            oxy-4-thiapentyl)-4-tri-                                                                       15-dihydroxy-3-thia-9-oxo-15,16-tri-                         methylsilyloxycyclopent-                                                                       methylene-16-(3-trifluoromethyl-                             2-en-1-one       phenoxy)-4,17,18,19,20-pentanor-13-                                           trans-prostenoic acid                        __________________________________________________________________________

EXAMPLE 186 Preparation of methyl nat(andent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-13-transprostadienoate

To an ethereal solution of 0.10 g of nat(andent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans-prostadienoicacid is added an excess of ethereal diazomethane. After 5 minutes theexcess diazomethane and the solvent is blown off with a stream ofnitrogen to give the titled methyl ester.

EXAMPLES 187-192

In the manner of Example 186 described above, the prostaglandins listedin Table VI are esterified with the indicated diazoalkanes.

                                      Table VI                                    __________________________________________________________________________         Prostaglandin of                                                         Example                                                                            Example  Diazoalkane                                                                           Product esterified prostaglandin                        __________________________________________________________________________    187  71       diazomethane                                                                          methyl nat-(and ent)-11α,16-dihydroxy-9-                                oxo-16,17-tetramethylene-18,19,20-trinor-                                     5-cis-13-trans-prostadienoate                           188  74       diazoethane                                                                           ethyl nat-(and ent-15R,16S)-11α,15-                                     dihydroxy-9-oxo-15,16-trimethylene-13-                                        trans-prostenoate                                       189  75       1-diazopropane                                                                        n-propyl nat-15S,16S-(and ent-15R,16S)-                                       11α,15-dihydroxy-9-oxo-15,16-trimethylene-                              13-trans-prostenoate                                    190  76       diazomethane                                                                          methyl-nat-(and ent)-11α,15-dihydroxy-9-                                oxo-15,16-tetramethylene-17,18,19,20-                                         tetranor-13-trans-prostenoate                           191  118      1-diazohexane                                                                         n-hexyl-nat-15S,16R-(and ent-15R,16S)-11α,-                             15-dihydroxy-9-oxo-15,16-trimethylene-5-                                      cis-13-trans-prostadienoate                             192  194      diazoethane                                                                           ethyl-nat-(and ent)-15-hydroxy-9-oxo-15,16-                                   tetramethylene-17,18,19,20-tetranor-5-cis-                                    10,13-trans-prostatrienoate                             __________________________________________________________________________

EXAMPLE 194 Preparation of nat-(andent)-15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-10,13-trans-prostatrienoicAcid

To 2.07 g (6.38 mmol) of 1-(2-iodovinyl)-1-trimethylsilyloxy cyclohexanein 3 ml of toluene is added with stirring under nitrogen at =40° C. 16.1ml of 0.8 M t-butyllithium in pentane. After 1 hour, 6 ml of ether isadded and the mixture is stirred at 25° C. for 25 minutes. The solutionis cooled to -78° C. and a solution of 0.842 g (6.45 mmol) of copperpentyne and 2.58 ml of hexamethylphosphorous triamide in 35 ml of etheris added. After 1 hour, 45 minutes, a solution of 2.35 g (6.38 mmol) of2-(6-carbotrimethylsilyloxyhex-2-cis-enyl)4-trimethylsilyloxycyclopent-2-en-1-one in 35 ml of ether is added.After stirring for 1 hour at -78° C. and 1 hour at 0° C., the mixture ispoured into dilute hydrochloric acid. The mixture is extracted withether. The ether is removed and the residue is dissolved in 14 ml ofacetic acid-tetrahydrofuran-water 4:2:1. After 1 hour the mixture ispoured into water and extracted with ether. The ether is removed. Theresidue is purified by dry column chromatography on silica gel elutingwith ether containing 0.75% acetic acid; 1.1 g of the subject compoundis obtained.

EXAMPLES 195-208

By allowing the conjugate addition mixtures to warm to 0° C. inaccordance with the methods described in Example 194 the products ofTable VII are prepared from the indicated vinyl iodides or vinyl tincompound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugateaddition, only one of the diastereoisomers is listed in Table VII. Itshould be understood that the other diastereoisomer is also formed whichin its nat and ent forms has an opposite (mirror image) configuration atthe assymmetric carbon atoms on the β-chain (the chain containing C₁₃-C₁₄ . . . etc.) to that of the respective nat and ent forms of thelisted diastereoisomer; both of these diastereoisomers are claimed inthe invention as well as their component enantiomers.

                                      Table VII                                   __________________________________________________________________________                                  Product 9-oxo-10,13-trans-prosta-                    Vinyl Iodide or Vinyl    dienoic and its diastereoisomer                 Example                                                                            Tin of Example                                                                           Cyclopent-2-en-1-one                                                                        where applicable (see hereinabove)              __________________________________________________________________________     195  29a       2-(6-carboxyethyl)-4-hy-                                                                    nat-15S,16R-(and ent-15R,16S)-15-                               droxycyclopent-2-en-1-one                                                                   hydroxy-9-oxo-15,16-trimethylene-                                             13-trans,10-prostadienoic acid                  196  36         2-(6-carboxyhexyl)-4-hy-                                                                    nat-15S,16S-(and ent-15R,16R)-15-                               droxycyclopent-2-en-1-one                                                                   hydroxy-9-oxo-15,16-trimethylene-                                             13-trans,10-prostadienoic acid                  197  31         2-(6-carboxyhexyl)-4-hy-                                                                    nat-(and ent)-15-hydroxy-9-oxo-                                 droxycyclopent-2-en-1-one                                                                   15,16-tetramethylene-17,18,19,20-                                             tetranor-13-trans,10-prostadienoic                                            acid                                            198  39         2-(6-carboxyhexyl)-4-hy-                                                                    nat-15R,16S-(and ent-15S,16R)-15-hy-                            droxycyclopent-2-en-1-one                                                                   droxy-9-oxo-15,16-trimethylene-16-                                            (3-trifluoromethylphenoxy)-17,18,-                                            19,20-tetranor-13-trans,10-prosta-                                            dienoic acid                                    199  40         2-(6-carboxyhexyl)-4-hy-                                                                    nat-15R,16R,-(and ent-15S,16S)-15-                              droxycyclopent-2-en-1-one                                                                   hydroxy-9-oxo-15,16-trimethylene-                                             16-(3-trifluoromethylphenoxy)-                                                17,18,19,20-tetranor-13-trans,10-                                             prostadienoic acid                              200  30         2-(6-carboxyhexyl)-4-hy-                                                                    nat-(and ent)-16-hydroxy-9-oxo-                                 droxycyclopent-2-en-1-one                                                                   16,17-tetramethylene-18,19,20-tri-                                            nor-13-trans,10-prostadienoic acid              201  42         2-(5-carboxypentyl)cyclo-                                                                   nat-15R,16R-(and ent-15S,16S)-15-                               pent-2-en-1-one                                                                             hydroxy-9-oxo-15,16-trimethylene-                                             16-(4-fluorophenoxy)-17,18,19,20-                                             21-pentanor-13-trans,10-prostadien-                                           oic acid                                        202   29a       2-(6-carboxyhex-2-cis-                                                                      nat-15S,16R-(and ent-15R,16S)-15-                               enyl)-4-hydroxycyclo-                                                                       hydroxy-9-oxo-15,16-trimethylene-                               pent-2-en-1-one                                                                             13-trans-5-cis,10-prostadienoic                                               acid                                            203  36         2-(6-carboxyhex-2-cis-                                                                      nat-15S,16S-(and ent-15R,16R)-15-                               enyl)-4-hydroxycyclo-                                                                       hydroxy-9-oxo-15,16-trimethylene-                               pent-2-en-1-one                                                                             13-trans-5-cis,10-prostatrienoic                                              acid                                            204  39         2-(6-carboxyhex-2-cis-                                                                      nat-15R,16S-(and ent-15S,16R)-15-                               enyl)-4-hydroxycyclo-                                                                       hydroxy-9-oxo-15,16-trimethylene-                               pent-2-en-1-one                                                                             16-(3-trifluoromethylphenoxy)-                                                17,18,19,20-tetranor-13-trans-5-                                              cis,10-prostatrienoic acid                      205  40         2-(6-carboxyhex-2-cis-                                                                      nat-15R,16R-(and ent-15S,16S)-15-                               enyl)-4-hydroxycyclo-                                                                       hydroxy-9-oxo-15,16-trimethylene-                               pent-2-en-1-one                                                                             16-(3-trifluoromethylphenoxy)-                                                17,18,19,20-tetranor-13-trans-5-                                              cis,10-prostatrienoic acid                      206  41         2-(6-carboxyhex-2-cis-                                                                      nat-15R,16S-(and ent-15S,16R)-15-                               enyl)-4-hydroxycyclo-                                                                       hydroxy-9-oxo-15,16-trimethylene-                               pent-2-en-1-one                                                                             16-(4-fluorophenoxy)-17,18,19,20-                                             tetranor-13-trans-5-cis,10-prosta-                                            trienoic acid                                   207  43         2-(6-carboxyhex-2-cis-                                                                      nat-15R,16S-(and ent-15S,16R)-15-                               enyl)-4-hydroxycyclo-                                                                       hydroxy-9-oxo-15,16-trimethylene-                               pent-2-en-1-one                                                                             16-(3-chlorophenoxy)-17,18,19,20-                                             tetranor-13-trans-5-cis,10-prosta-                                            trienoic acid                                   208  30         2-(6-carboxyhex-2-cis-                                                                      nat-(and ent)-16-hydroxy-9-oxo-16,-                             enyl)-4-hydroxycyclo-                                                                       17-tetramethylene-18,19,20-trinor-                              pent-2-en-1-one                                                                             13-trans-5-cis,10-prostatrienoic                                              acid                                            __________________________________________________________________________

EXAMPLE 209 Preparation of nat-(andent)-15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-10,13-trans-prostadienoicacid

A solution of 1.5 g of nat-(andent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostenoicacid 80 ml of 0.5N hydrochloric acid in 1:1 tetrahydrofuran-water isallowed to stand at room temperature under argon for 72 hours. Thesolution is treated with brine and extracted with ether. The extract iswashed with brine and dried with anhydrous magnesium sulfate. Theresidue remaining after evaporation of the solvent is purified by drycolumn chromatography on silica gel to give the product as an oil.

EXAMPLE 210 Preparation of nat(andent)-16-Hydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis-10,13-trans-prostatrienoicAcid

A 40 mg portion of nat(andent)-11α,16-dihydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-5-cis-13-trans-prostadienoicacid is dissolved in 5 ml of 0.5N hydrochloric acid intetrahydrofuran-water (prepared by diluting 5 ml of 1N hydrochloric acidto 10 ml with tetrahydrofuran) with stirring under nitrogen at roomtemperature for 3 days. The mixture is poured into saturated sodiumchloride solution and extracted with ether. The ether extract is washedwith water and brine and the solvent is evaporated. The dried residue isspotted on a thin layer chromatography plate and developed with 40%ethyl acetate:0.5% acetic acid in hexane twice. The product is recoveredin ethyl acetate.

EXAMPLES 211-225

Treatment of the 11α,9-oxo-prostenoic acids listed in Table VIII belowwith dilute acid in accordance with the method described in Examples 209and 210 furnishes the products of the table.

                                      Table VIII                                  __________________________________________________________________________         11α-hydroxy-9-oxo-pros-                                            Example                                                                            taglandin of Example                                                                      Product 9-oxo-10,13-trans-prostaglandin                      __________________________________________________________________________    211  131         nat-15R,16R-(and ent-15S,16S)-15-hydroxy-                                     9-oxo-15,16-trimethylene-16-(3-chloro-                                        phenoxy)-17,18,19,20-tetranor-10,13-trans-                                    5-cis-prostadienoic acid                                     212  136         nat-16R,17S-(and ent-16S,17R)-16-hydroxy-                                     9-oxo-16,17-trimethylene-17-(3-trifluoro-                                     methylphenoxy)-18,19,20-trinor-10,13-                                         trans-5-cis-prostadienoic acid                               213  137         nat-16R,17R-(and ent-16S,17S)-16-hydroxy-                                     9-oxo-16,17-trimethylene-17-(3-trifluoro-                                     methylphenoxy)-18,19,20-trinor-10,13-                                         trans-5-cis-prostadienoic acid                               214  138         nat-15S,16R-(and ent-15R,16S)-15-hydroxy-                                     9-oxo-15,16-trimethylene-1a,1b-dihomo-                                        10,13-trans-5-cis-prostadienoic acid                         215  140         nat-(and ent-)-15-hydroxy-9-oxo-15,16-                                        tetramethylene-1a,1b-dihomo-17,18,19,                                         20-tetranor-10,13-trans-5-cis-prost-                                          dienoic acid                                                 216  146         nat-15S,16S-(and ent-15R,16R)-15-hydroxy-                                     9-oxo-3-oxa-15,16-trimethylene-10,13-                                         trans-prostenoic acid.                                       217  147         nat-(and ent)-15-hydroxy-9-oxo-3-oxa-15,16-                                   tetramethylene-17,18,19,20-tetranor-10,13-                                    trans-prostenoic acid.                                       218  151         nat-15S,17S-(and ent-15R,17R)-15-hydroxy-                                     9-oxo-4-methyl-15,17-trimethylene-19,20-                                      dinor-10,13-trans-prostenoic acid.                           219  156         nat-methyl-15S,16R-15-hydroxy-9-oxo-15,16-                                    trimethylene-10,13-trans-prostenoate                         220  158         nat-methyl-15-hydroxy-9-oxo-15,16-tetra-                                      methylene-17,18,19,20-tetranor-10,13-trans-                                   prostenoate                                                  221  159         nat-methyl-16-hydroxy-9-oxo-16,17-tetra-                                      methylene-18,19,20-trinor-10,13-trans-                                        prostenoate                                                  222  163         ent-methyl-15R,16R-15-hydroxy-9-oxo-                                          15,16-trimethylene-10,13-trans-prosten-                                       oate                                                         223  168         nat-methyl-15S,16R-15-hydroxy-9-oxo-                                          15,16-trimethylene-10,13-trans-5-cis-                                         prostadienoate                                               224  172         nat-methyl-15R,16S-15-hydroxy-9-oxo-                                          15,16-trimethylene-16-(3-trifluoro-                                           methylphenoxy)-17,18,19,20-tetranor-                                          10,13-trans-5-cis-prostadienoate                             225  173         nat-methyl-15R,16R-15-hydroxy-9-oxo-15,16-                                    trimethylene-16-(3-trifluoromethylphenoxy)                   17,18,19,20-tetranor-10,13-trans-5-cis-                                                        prostadienoate                                               __________________________________________________________________________

EXAMPLE 227 Preparation of nat(andent)-15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis,8,13-trans-prostatrienoicacid

A solution of 0.70 g of potassium carbonate and 0.40 g of nat(andent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans-prostadienoicacid in 200 ml of methanol-water 5:5 is allowed to stand at roomtemperature for 24 hours. The solution is diluted with water andacidified with hydrochloric acid. The solution is extracted with ether.The ether layer is dried over magnesium sulfate. The solvent is removedgiving the titled compound as an oil.

EXAMPLES 228-233

In the mamner described above in Example 227 the 11α-hydroxy compoundslisted in Table IX are treated with potassium carbonate to give thelisted Δ⁸(12) derivatives.

EXAMPLE 234 Preparation of nat(and ent)-11α/βCyano-15-hydroxy-9-ozxo-15,16-tetramethylene-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic Acid

A mixture of 0.45 g of nat(andent)-15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans,5-cis,10-prostatrienoicacid, 0.68 g of acetone cyanohydrin and 0.143 g of sodium carbonate inone ml of methanol and one ml of water is stirred at reflux undernitrogen for 2 hours. The solution is then stirred overnight. Theresulting dark solution is diluted with water, acidified with HCL andextracted with ether. The ether solution is dried with MgSO₄ andactivated charcoal and filtered through a pad of silica gel. The solventis removed giving 0.37 g of the desired product.

EXAMPLES 235-243

In the manner described above for Example 234, the 11α/βcyanoderivatives listed in Table X are prepared from the listed Δ¹⁰derivatives.

                  Table IX                                                        ______________________________________                                               11α-hydroxy prostaglan-                                          Example                                                                              din of Example  Δ.sup.8(12) -prostaglandin                       ______________________________________                                        228    71              nat-(and ent)-16-hydroxy-                                                     9-oxo-16,17-tetramethylene-                                                   18,19,20-trinor-8,13-trans,5-                                                 cis-prostatrienoic acid                                229    74              nat-15S,16R-(and ent-                                                         15R,16S)-15-hydroxy-9-oxo-                                                    15,16-trimethylene-8,                                                         13-trans-prostadienoic acid                            230    75              nat-15S,16S-(and ent-                                                         15R,16R)-15-hydroxy-9-oxo-                                                    15,16-trimethylene-8,                                                         13-trans-prostadienoic acid                            231    76              nat-(and ent)-15-hydroxy-                                                     9-oxo-15,16-tetramethylene-                                                   17,18,19,20-tetranor-8,                                                       13-trans-prostadienoic acid                            232    118             nat-15S,16R-(and ent-15R,                                                     16S)-15-hydroxy-9-oxo-15,-                                                    16-trimethylene-8,13-trans-                                                   5-cis-prostatrienoic acid                              233    119             nat-15S,16S-(and ent-15R,                                                     16R)-15-hydroxy-9-oxo-15,-                                                    16-trimethylene-8,13-trans,                                                   5-cis-prostatrienoic acid                              ______________________________________                                    

                  Table X                                                         ______________________________________                                               Δ.sup.10 Derivative of                                           Example                                                                              Example      11α/β Cyano prostaglandin                      ______________________________________                                        235    195          nat-15S,16R-(and ent-                                                         15R,16S)-11α/β-cyano-15-hy-                                        droxy-9-oxo-15,16-trimethyl-                                                  lene-13-trans-prostenoic acid                             236    196          nat-15S,16S-(and ent-                                                         15R,16R)-11α/β-cyano-15-hy-                                        droxy-9-oxo-15,16-trimethyl-                                                  lene-13-trans-prostenoic acid                             237    197          nat-(and ent)-11α/β-cyano-                                         15-hydroxy-9-oxo-15,16-                                                       tetramethylene-17,18,19,                                                      20-tetranor-13-trans-                                                         prostenoic acid                                           238    198          nat-15R,16s-(and ent-15S,                                                     16R)-11α/β-cyano-15-hy-                                            droxy-9-oxo-15,16-tri-                                                        methylene-16-(3-trifluoro-                                                    methylphenoxy)-17,18,19,                                                      20-tetranor-13-trans-                                                         prostadienoic acid                                        239    199          nat-15R,16R-(and ent-                                                         15S,16S)-11α/β-cyano-15-hy-                                        droxy-9-oxo-15,16-tri-                                                        methylene-16-(3-trifluoro-                                                    methylphenoxy)-17,18,19,                                                      20-tetranor-13-trans-                                                         prostenoic acid                                           240    200          nat-(and ent)-11α/β-cyano-                                         16-hydroxy-9-oxo-16,17-                                                       tetramethylene-18,19,                                                         20-trinor-13-trans-pros-                                                      tenoic acid                                               241    210          nat-(and ent)-11-α/β-cyano-                                        16-hydroxy-9-oxo-16,17-                                                       tetramethylene-18,19,                                                         20-trinor-13-trans,5-cis-                                                     prostadienoic acid                                        242    209          nat-(and ent)-11α/β-cyano-                                         15-hydroxy-9-oxo-15,16-                                                       tetramethylene-17,18,19,                                                      20-tetranor-13-trans-                                                         prostenoic acid                                           243    213          nat-16R,17R-(and ent-                                                         16S,17S)-11α/β-cyano-16-hy-                                        droxy-9-oxo-16,17-tri-                                                        methylene-17-(3-trifluoro-                                                    methylphenoxy)-18,19,                                                         20-trinor-13-trans-5-cis-                                                     prostenoic acid                                           ______________________________________                                    

EXAMPLE 244 Preparation of2-(6-Carbotrimethylsilyloxyhex-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one

To a solution of one g of2-(6-carboxyhex-2-cis-enyl)-4-hydroxycyclopent-2-en-1-one in 12.5 ml ofdry pyridine at 15° C. under argon is added with stirring 3.3 ml ofhexamethyldisilazane (HMDS) followed by dropwise addition of 1.6 ml oftrimethylchlorosilane (TMCS). The resulting mixture is stirred atambient temperature for one hour then taken to dryness (vac. pump). Theresidue is taken up in hexanes and filtered thru Celite. Evaporation ofthe mother liquor followed by two evaporations with toluene furnished1.5 g (96%) of pure2-(6-carbotrimethylsilyloxyhex-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-1-one.

EXAMPLE 245 Preparation of2-(6-Carbotrimethylsilyloxyhexyl)-4-trimethylsilyloxycyclopent-2-en-1-one

To a solution of one g of2-(6-carboxyhexyl)-4-hydroxycyclopent-2-en-1-one in 12.5 ml of drypyridine at 15° C. under argon, is added with stirring 3.3 ml ofhexamethyldisilazane followed by dropwise addition of 1.6 ml oftrimethylchlorosilane. The resulting mixture is stirred at ambienttemperature for one hour and then taken to dryness. The residue is takenup in hexane and filtered through diatomaceous earth. Evaporation of themother liquor followed by two evaporations with toluene gives pureproduct.

EXAMPLE 246 Preparation of2-(6-carbomethoxyhexyl)-4-trimethylsilyloxcyclopent-2-en-1-one

To a solution of 1.0 g of2-(6-carbomethylhexyl)-4(R)-hydroxycyclopent-2-en-1-one [R. Pappo, etal., Tetrahedron Letters, 943 (1973)]in 12.5 ml of dry pyridine at 15°0under argon was added with stirring 3.3 ml (24 mmoles) ofhexamethyldisilazane (HMDS) followed by dropwise addition of 1.6 ml(20.5 mmoles) of trimethylchlorosilane (TMCS). The resulting mixture wasstirred at ambient temperature for 1 hour then taken to dryness (vac.pump.). The residue is taken up in hexanes and filtered thru Celite.Evaporation of the mother liquor followed by two evaporations withtoluene furnished2-(6-carbomethoxyhexyl)-4(R)-trimethylsilyloxycyclopent-2-en-1-one.

EXAMPLE 247 Preparation of 2-(6-carbomethoxyhexyl)-4(S)-trimethylsilyloxycyclopent-2-en-1-one

In the manner described in Example 239, treatment of2-(6-carbomethoxyhexyl)-4-(S)-hydroxycyclopent-2-en-1-one [R.Pappo, etal., Tetrahedron Letters, 943 (1973)] with hexamethyldisilazane andtrimethylsilylchloride gives the subject product.

EXAMPLE 248 Preparation of 5-chloro-1-(2-furyl)-1-pentanol

To a stirred suspension of 2-furyllithium (prepared from 0.53 moles ofn-butyllithium and 39.5 g of furan by the procedure of J. Org. Chem.,27, 1216 (1962) ) in 350 ml of ether and ca. 200 ml of hexane at -78° isadded a solution of 57.9 g of 5-chloropentanol (Chem. Abstr., 59, 7579F(1963) ) in 80 ml of ether during 25 minutes. The mixture is warmed to0° during 20 minutes, stirred at 0° for 15 minutes, and treated with 140ml of saturated ammonium chloride. The ether phase is washed with waterand brine, dried over magnesium sulfate and potassium carbonate mixture,and concentrated to give a liquid, pmr spectrum (CDCl₃): δ3.59 (triplet,CH₂ Cl₂) and 4.70 (triplet, CH₂ CHOH).

EXAMPLE 249 Preparation of5-(carbethoxymethylthio)-1-(2-furyl)-1-pentanol

To a stirred, refluxing mixture of 76 g of ethyl mercaptoacetate, 79.5 gof 5-chloro-1-(2-furyl)-1-pentanol (Example 248 ), and 10 ml of 1.5Msodium ethoxide in ethanol is added an additionan 300 ml of 1.5M sodiumethoxide during 15 minutes. The resulting mixture is stirred at refluxfor 3 hours, cooled, and concentrated to remove most of the ethanol. Theresidue is partitioned with ether and water. The ether phase is washedwith brine and dried over potassium carbonate. The solution isconcentrated, diluted with xylene, and again concentrated to give anoil, pmr spectrum (CDCl₃): δ3.24 (singlet, --S--CH₂ CO₂ C₂ H₅) and 4.70(triplet, CH₂ CHOH).

EXAMPLE 250 Preparation of 2-(6-carboxy-5-thiahexyl)-4-hydroxycyclopent-2-en-1-one

stirred solution of 125 g of 5-(carbethoxymethylthio)-1-(2-furyl)-1-pentanol (Example 249), 22.4 g of sodium formate, 250 mlof formic acid, and 400 mg of hydroquinone in 2000 ml of dioxane and1330 ml of water is refluxed for 20 hours.

The solution, containing crude3-hydroxy-2-[4-(carbethoxymethylthio)butyl]cyclopent-4-en-1-one, iscooled and treated during 10 minutes with 75 ml of sulfuric acid(d=1.84) with stirring. The stirred solution is reluxed for 16 hours,cooled, saturated with sodium chloride, and extracted with ethylacetate. The extract is washed with brine, dried over magnesium sulfate,and concentrated. The residue is subjected to chromatography on silicagel with chloroform progressively enriched in ether, ether, and etherprogressively enriched in acetone to afford the subject compound as anoil, pmr spectrum (CDCl₃):δ3.24 (singlet, --S--CH₂ --CO₂ C₂ H₅), 5.0(broad singlet --CHOH--).

EXAMPLE 251 Preparation of2-(6-carbotrimethylsilyloxy-5-thiahexyl)-4-trimethylsiloxycyclopent-2-en-1-one

To a stirred solution of 28.4 g of4-hydroxy-2-[4-(carboxymethylthio)butyl]cyclopent-2-en-1-one (Example57) and 76 ml of hexamethyldisiliazane in 330 ml of pyridine at 5° isadded 38 ml of chlorotrimethylsilane during 5 minutes. The mixture isstirred at ambient temperature for 3.5 hours, at 45° for 5 minutes, andthen evaporated to remove solvent. The residue is stirred with 1000 mlof petroleum ether and filtered. The filtrate is treated with charcoaland filtered; this filtrate is concentrated with the aid of toluene togive a liquid, pmr spectrum (CDCl₃): δ0.18 (singlet, trimethylsiloxygroup) and 0.28 (singlet, trimethylsiloxycarbonyl group).

EXAMPLE 252 Preparation of 4-chloro-1-(2-furyl)-1-butanol

To a stirred suspension of 2-furyllithium (prepared from 0.53 moles ofn-butyllithium and 39.5 g of furan by the procedure of J. Org. Chem.,27, 1216 (1962)) in 350 ml of ether and ca. 200 ml of hexane at -78° isadded a solution of 57.9 g of 4-chlorobutanol (Chem. Abstr., 59, 7579F(1963)) in 80 ml of ether during 25 minutes. The mixture is warmed to 0°during 20 minutes, stirred at 0° for 15 minutes, and treated with 140 mlof saturated ammonium chloride. The ether phase is washed with water andbrine, dried over magnesium sulfate and potassium carbonate mixture, andconcentrated to give a liquid, pmr spectrum (CDCl₃):δ3.59 (triplet, CH₂Cl) and 4.70 (triplet, CH₂ CHOH).

EXAMPLE 253 Preparation of 4-carbethoxymethylthio)-1-(2-furyl)-1-butanol

To a stirred, refluxing mixture of 76 g of ethyl mercaptoacetate, 79.5 gof 4-chloro-1-(2-furyl)-1-butanol (Example 59), and 10 ml of 1.5M sodiumethoxide in ethanol is added an additional 300 ml of 1.5M sodiumethoxide during 15 minutes. The resulting mixture is stirred at refluxfor 3 hours, cooled, and concentrated to remove most of the ethanol. Theresidue is partitioned with ether and water. The ether phase is washedwith brine and dried over potassium carbonate. The solution isconcentrated, diluted with xylene, and again concentrated to give anoil, pmr spectrum (CDCl₃): δ3.24 (singlet, --S--CH₂ --CO₂ C₂ H₅) and4.70 (triplet, CH₂ CHOH).

EXAMPLE 254 Preparation of2-(5-carboxy-4-thiapentyl)-4-hydroxycyclopent-2-en-1-one

A stirred solution of 125 g of4-(carbethoxymethylthio)-1-(2-furyl)-1-butanol (Example 60), 22.4 g ofsodium formate, 250 ml of formic acid, and 400 mg of hydroquinone in2000 ml of dioxane and 1330 ml of water is refluxed for 20 hours.

The solution, containing crude3-hydroxy-2-[3-(carbethoxymethylthio)propyl]cyclopent-4-en-1-one, iscooled and treated during 10 minutes with 75 ml of sulfuric acid(d=1.84) with stirring. The stirred solution is refluxed for 16 hours,cooled, saturated with sodium chloride, and extracted with ethylacetate. The extract is washed with brine, dried over magnesium sulfate,and concentrated. The residue is subjected to chromatography on silicagel with chloroform progressively enriched in ether, ether, and etherprogressively enriched in acetone to afford the subject compound as anoil.

EXAMPLE 255 Preparation of2-(5-carbotrimethylsilyloxy-4-thiapentyl)-4-trimethylsiloxycyclopent-2-en-1-one

To a stirred solution of 28.4 g of4-hydroxy-2-[4-(carboxymethylthio)butyl]cyclopent-2-en-1-one (Example57) and 76 ml of hexamethyldisilazane in 330 ml of pyridine at 5° isadded 38 ml of chlorotrimethylsilane during 5 minutes. The mixture isstirred at ambient temperature for 3.5 hours, at 45° for 5 minutes, andthen evaporated to remove solvent. The residue is slurried with 1000 mlof petroleum ether and filtered. The filtrate is treated with charcoaland filtered; this filtrate is concentrated with the aid of toluene togive a liquid, pmr spectrum (CDCl₃):δ0.18 (singlet, trimethylsiloxygroup) and 0.28 (singlet, trimethylsiloxycarbonyl group).

EXAMPLE 256 Preparation of nat(andent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranorprostanoic acid

A solution of nat(andent)-11α,15-dihydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-13-trans-prostanoicacid (800 mg) in 50 ml of ethyl acetate is hydrogenated in a Parrapparatus using 500 mg of 5% rhodium-on-carbon. The catalyst is removedby filtration and the filtrate is taken to dryness to furnish of thetitled product.

EXAMPLES 257-259

Hydrogenation of the prostenoic acids listed in Table XI below in ethylacetate using a rhodium-on-carbon catalyst in accordance with the methoddescribed in Example 63 gives the prostanoic acids of the table.

                                      Table XI                                    __________________________________________________________________________         13-trans-prostenoic acid                                                 Example                                                                            of Example  Prostanoic Acid                                              __________________________________________________________________________    257  72          nat-15S,16R-(and ent-15R,16S)-11α,15-dihydroxy-                         9-oxo-15,16-trimethylene prostanoic acid                     258  73          nat-15S,16S-(and ent-15R,16R)-11α,15-dihydroxy-                         9-oxo-15,16-trimethylene prostanoic acid                     259  83          nat-(and ent)-11α,16-dihydroxy-9-oxo-16,17-tetra-                       methylene-18,19,20-trinor prostanoic acid                    __________________________________________________________________________

We claim:
 1. An optically active compound of the formula: ##STR27##wherein R₁ is selected from the group consisting of hydroxy and C₁ -C₆alkoxy; Y is a trivalent radical selected from the group consisting of amoiety of the formula ##STR28## X is a divalent radical selected fromthe group consisting of a moiety of the formula ##STR29## wherein R₄ isselected from the group consisting of C₁ -C₇ alkyl, hydrogen; n is zeroor an integer from 1 to 4; m is zero or an integer from 1 to 4, with theproviso that the sum of n and m has the value of 2 to 4; w is zero or 1;Z is a divalent radical selected from the group consisting of a moietyof the formula --(CH₂)p--, --(CH₂)_(t) --O--CH₂ --, and --(CH₂)_(t)--S--CH₂ --, wherein p is an integer from 5 to 7, and t is an integerfrom 3 to 5; the racemic mixture thereof; the mirror image thereof; andthe pharmacologically acceptable cationic salts thereof when R₁ ishydrogen.
 2. The compound according to claim 1, wherein t is
 4. 3. Thecompound according to claim 2, wherein p is
 6. 4. The compound accordingto claim 3, wherein Z is --(CH₂)₄ --O--CH₂ --.
 5. The compound accordingto claim 3 wherein Z is --(CH₂)₄ --S--CH₂ --.
 6. The compound accordingto claim 3, wherein Z is --(CH₂)₆ --.
 7. The compound according to claim6, wherein w is zero.
 8. The compound according to claim 6, wherein w isone.
 9. A compound according to claim 4, nat-15S-16S-(andent-15R,16R)-15-hydroxy-9-oxo-3-oxa-15,16-trimethylene-10,13-trans-prostadienoic acid.
 10. A compound according toclaim 4, methyl nat-15S, 16S-(andent-15R,16R)-15-hydroxy-9-oxo-3-oxa-15,16-trimethylene-10,13-trans-prostadienoate.11. A compound according to claim 4, nat-(andent)-15-hydroxy-9-oxo-3-oxa-15,16-trimethylene-17,18,19,20-tetranor-10,13-trans-prostadienoicacid.
 12. A compound according to claim 7, nat-15S,16R-(andent-15R,16S)-15-hydroxy-9-oxo-15,16-trimethylene-10,13-trans-prostadienoicacid.
 13. A compound according to claim 7,nat-15S,16R-15-hydroxy-9-oxo-15,16-trimethylene-10,13-trans-prostadienoicacid.
 14. A compound according to claim 7, methyl nat-15S,16R-(andent-15R,16S)-15-hydroxy-9-oxo-15,16-trimethylene-10,13-trans-prostadienoate.15. A compound according to claim 7, methylnat-15S,16R-15-hydroxy-9-oxo-15,16-trimethylene-10,13-trans-prostadienoate16. A compound according to claim 7, nat-15S,16S-(andent-15R,16R)-15-hydroxy-9-oxo-15,16-trimethylene-10,13-trans-prostadienoicacid.
 17. A compound according to claim 7,nat-15S,16S-15-hydroxy-9-oxo-15,16-trimethylene-10,13-trans-prostadienoicacid.
 18. A compound according to claim 7, methyl nat-15S,16S-(and ent15R,16R)-15-hydroxy-9-oxo-15,16-trimethylene-10,13-trans-prostadienoate.19. A compound according to claim 7, methylnat-15S,16S-15-hydroxy-9-oxo-15,16-trimethylene-10,13-trans-prostadienoate.20. A compound according to claim 7, nat-(andent)-15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-10,13-trans-prostadienoicacid.
 21. A compound according to claim 7,nat-15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-10,13-trans-prostadienoicacid.
 22. A compound according to claim 7, methyl nat-(andent)-15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-10,13-trans-prostadienoate.23. A compound according to claim 7, methylnat-15-hydroxy-9-oxo-15,16-tetramethylene-17,18,19,20-tetranor-10,13-trans-prostadienoate.24. A compound according to claim 7, nat-(andent)-15-hydroxy-9-oxo-15,16-trimethylene-17,18,19,20-tetranor-10,13-trans-prostadienoicacid.
 25. A compound according to claim 7,nat-15-hydroxy-9-oxo-15,16-trimethylene-17,18,19,20-tetranor-10,13-trans-prostadienoicacid.
 26. A compound according to claim 7, nat-(andent)-15-hydroxy-9-oxo-15,16-pentamethylene-17,18,19,20-tetranor-10,13-trans-prostadienoicacid.
 27. A compound according to claim 7,nat-15-hydroxy-9-oxo-15,16-pentamethylene-17,18,19,20-tetranor-10,13-trans-prostadienoicacid.
 28. A compound according to claim 7, nat-15S,17R-(andent-15R,17S)-15-hydroxy-9-oxo-15,17-dimethylene-10,13-trans-prostadienoicacid.
 29. A compound according to claim 7,nat-15S,17R-15-hydroxy-9-oxo-15,17-dimethylene-10,13-trans-prostadienoicacid.
 30. A compound according to claim 7, nat-15S,17S-(and-ent-15R,17R)-15-hydroxy-9-oxo-15,17-dimethylene-10,13-trans-prostadienoicacid.
 31. A compound according to claim 7,nat-15S,17S-15-hydroxy-9-oxo-15,17-dimethylene-10,13-trans-prostadienoic acid.
 32. A compound according toclaim 7, nat-15S,17R-(andent-15R,17S)-15-hydroxy-9-oxo-15,17-trimethylene-19,20-dinor-10,13-trans-prostadienoicacid.
 33. A compound according to claim 7,nat-15S,17R-15-hydroxy-9-oxo-15,17-trimethylene-19,20-dinor-10,13-trans-prostadienoicacid.
 34. A compound according to claim 7, nat-15S,17S-(andent-15R,17R)-15-hydroxy-9-oxo-15,17-trimethylene-19,20-dinor-10,13-trans-prostadienoicacid.
 35. A compound according to claim 7,nat-15S,17S-15-hydroxy-9-oxo-15,17-trimethylene-19,20-dinor-10,13-transprostadienoic acid.
 36. A compound according to claim 7, nat-15S,16R-(andent-15R,16S)-15-hydroxy-9-oxo-15,16-tetramethylene-10,13-trans-prostadienoicacid.
 37. A compound according to claim 7,nat-15S,16R-15-hydroxy-9-oxo-15,16-tetramethylene-10,13-trans-prostadienoicacid.
 38. A compound according to claim 7, nat-15S,16S-(andent-15R,16R)-15-hydroxy-9-oxo-15,16-tetramethylene-10,13-trans-prostadienoicacid.
 39. A compound according to claim 7,nat-15S,16S-15-hydroxy-9-oxo-15,16-tetramethylene-10,13-trans-prostadienoicacid.
 40. A compound according to claim 8, nat-(andent)-16-hydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-10,13-trans-prostadienoicacid.
 41. A compound according to claim 8,nat-16-hydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-10,13-trans-prostadienoicacid.
 42. A compound according to claim 8, methyl nat-(andent)-16-hydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-10,13-trans-prostadienoate.43. A compound according to claim 8, methylnat-16-hydroxy-9-oxo-16,17-tetramethylene-18,19,20-trinor-10,13-trans-prostadienoate.44. A compound according to claim 8, nat-16R,17S-(andent-16S,17R)-16-hydroxy-9-oxo-16,17-trimethylene-20-methyl-10,13-trans-prostadienoicacid.
 45. A compound according to claim 8,nat-16R,17S-16-hydroxy-9-oxo-16,17-trimethylene-20-methyl-10,13-trans-prostadienoicacid.
 46. A compound according to claim 8, nat-16R,17R-(andent-16S,17S)-16-hydroxy-9-oxo-16,17-trimethylene-20-methyl-10,13-trans-prostadienoicacid.
 47. A compound according to claim 8,nat-16R,17R-16-hydroxy-9-oxo-16,17-trimethylene-20-methyl-10,13-trans-prostadienoicacid.